Download technical bulletin reaction solvent dimethyl sulfoxide (dmso)

TECHNICAL BULLETIN
REACTION SOLVENT
DIMETHYL SULFOXIDE (DMSO)
O
S
H3C
CH3
CAS Name: Methane, sulfinylb is
CAS Registry Number: 67- 68- 5
Dimethyl sulfoxide as manufactured by Gaylord Chemical, is a water-white almost odorless liquid, boiling at
189°C. and melting at above 18.2° C. It is relatively stable and easy to recover, miscible in all proportions with
water and most common organic solvents and has a low order of toxicity.
Gaylord Chemical Corporation
P.O. Box 1209
Slidell, LA 70459-1209
(985) 649-5464
1
TABLE OF CONTENTS
INTRODUCTION
PART I.
PROPERTIES OF DMSO
Physical Properties
Thermal and Chemical Stability
Recovery from Aqueous Solutions
Page
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PART II.
SOLVENCY CHARACTERISTICS OF D MSO
Solubility of Salts
Solubility of Resins and Polymers
Solubility of Miscellaneous Materials
Solubility of Gases
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PART III.
REACTIONS OF DMSO
1. Oxidation of DMSO
2. Reduction of DMSO
3. Reaction with Metals
4. Reaction with Strong Bases -Dimsyl Ion
5. Reaction with Acid Halides
6. Reaction with Acid Anhydrides
7. Halogenation of DMSO
8. Reaction with Phenols and Aniline
9. Alcohol Oxidation with DMSO
a) Acetic Anhydride
b) Trifluoroacetic Anhydride
c) Dicyclohexylcarbodiimide
d) Phosphorus Pentoxide
e) Sulfur Trioxide-Pyridine
f) Oxalyl Chloride
10. Kornblum Reaction
11. Mehoxydimethylsulfonium Salts and
Trimethyloxosulfonium Salts
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PART IV.
DMSO AS A REACTION SOLVENT
A. DISPLACEMENT REACTIONS IN DMSO
Anions-Nucleophiles (Bases):
1. Acetylide Ion
2. Alkoxide Ion
3. Amides
4. Amines
5. Ammonia
6. Azide Ion
7. Carbanions
8. Carboxylate Ion
9. Cyanate Ion
10.Cyanide Ion
11.Halogen Ion
12.Hydroxide ion
13.Mercaptide (or Thiopenoxide) Ion
14.Nitrite Ion
15.Phenoxide Ion
16.Sulfide (or Hydrosulfide) and Thiosulfate Ions
17.Thiocyanate Ion
B. BASES AND BASE CATALYZED REACTIONS IN DMSO
Bacities in DMSO
Proton Removal
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1.
2.
3.
4.
5.
ELIMINATION REACTIONS
Cope Elimination
Decarboxylatoin and Decarbalkoxylation
Dehalogenation
Dehydrohalogenation
Nitrogen Elimination
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Page
1.
2.
3.
4.
1.
2.
3.
6. Sulfenate Elimination
7. Sulfonate Elimination
8. Water Elimination-dehydration
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ISOMERIZATION REACTIONS
1. Acetylene Isomerization
2. Allyl Group Isomerization
3. Diene, Triene Isomerization
4. Olefin Isomerization
5. Racemization
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C. OTHER REACTIONS IN D MSO
ADDITION REACTIONS
a) Additions to acetylenes
b) Additions to olefins
c) Additions to nitriles
d) Additions to isocyanates
CONDENSATION REACTIONS
a) Aldol-type condensations
b) Ester condensations
c) Dieckmann condensation-cyclization
d) Mannich reaction
e) Michael condensation
f) Reformatsky reaction
g) Thorpe-Ziegler condensation
h) Ullmann-type condens ations
i) Wittig reaction
OXIDATION REACTIONS
a) Autoxidation
b) Chemiluminescence
c) Other oxidations involving oxygen
d) Dehydrogenation
e) Hypohalite oxidations
f) Lead tetraacetate oxidations
g) Silver compound oxidations
h) Superoxide and peroxide oxidations
REDUCTION REACTIONS
Reduction of Alkyl Halides and Sulfonates
a) Reductions with sodium borohydride
b) Reductions with chromous ion
c) Reductions with dimsyl ion
d) Reductions with hydrazine
e) Reductions by electrolysis
Reduction of Carbonyl Compounds
a) Reductions with borohydrides
b) Catalytic reduction
c) Electrochemical reduction
d) Wolff-Kishner reduction
Reduction of Nitroaromatics
Reduction of C=C Systems
SOLVOLYTIC REACTIONS
Hydrolysis
a) Aliphatic halide hydrolysis
b) Aromatic halide hydrolysis
c) Amide hydrolysis
d) Epoxide hydrolysis
e) Ether hydrolysis
f) Nitrile hydrolysis
g) Saponification
Alcoholysis, Aminolysis
Transesterification (Ester Interchange)
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3
PART V.
PART VI.
PART VII.
USES OF DMSO
1. Polymerization and Spinning Solvent
Polymerization Solvent for Heat-Resistant Polymers
2. Extraction Solvent
3. Solvent for Electrolytic Reactions
4. Cellulose Solvent
5. Pesticide Solvent
6. Cleanup Solvent
7. Sulfiding Agent
8. Integrated Circuits
TOXICITY, HANDLING, HAZARDS, ANALYSIS
1. Toxicity and Handling Precautions
2. Comparative Toxicity of Commercial Solvents
3. Chemical Reactions to be Avoided with DMSO
4. Analytical Procedures
a) Gas chromatographic analysis of DMSO
b) DMSO freezing point
c) Water by Karl Fischer titration
BIBLIOGRAPHY
Page
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TABLES AND FIGURES
Table I
Table II
Table III
Table IV
Table V
Table VI
Table VII
Table VIII
Table IX
Table X
Table XI
Table XII
Table XIII
Physical Properties of DMSO
Results of Reflux of DMSO for 24 Hours with Various Compounds
Refluxing of DMSO and Mixtures for Shorter Periods
Effect of Heating DMSO with Concentrated Acids
Solubility of Salts in DMSO
Solubility of Resins and Polymers in DMSO
Solubility of Miscellaneous Materials in DMSO
Solubility of Gases in DMSO
Solubility of Various Bases in DMSO
Solubility of Sodium Azide in Four Solvents
Acidities in DMSO
Single-Dose Toxicity (Rats) of Some Common Solvents
Single-Dose Toxicities to Mice of 4M Solvents
Page
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Figure 1
Figure 2a
Figure 2b
Figure 3
Figure 4
Figure 5
Figure 6
Figure 7
Figure 8
Figure 9
Figure 10
Vapor Pressure-Temperature DMSO
Freezing Point Curve for DMSO-Water Solutions (Wt % water)
Freezing Point Curve for DMSO-Water Solution (Wt % water)
Viscosity of DMSO
Viscosity of DMSO-Water Solutions
Thermal Stability of DMSO
DMSO Recovery from Aqueous Solutions
Solubility of NaCN in DMSO
Solubility of NaCl in DMSO-H2O Mixtures
Solubility of Hydroxides in Aqueous DMSO
Acidity Functions of Bases in DMSO
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INTRODUCTION
Dimethyl sulfoxide or DMSO is a highly polar, high boiling, aprotic, water miscible, hygroscopic organic liquid. It is essentially odorless,
water white and has a low order of toxicity.
Chemically, DMSO is stable above 100° C in alkaline, acidic or neutral conditions. Prolonged refluxing at atmospheric pressure will
cause slow decomposition of DMSO. If this occurs, it can be readily detected by the odor of trace amounts of methyl mercaptan and
bis(methylthio)methane. The rate of decomposition is a timetemperature function that can be accelerated by the addition of acids and
retarded by some bases.
DMSO is a versatile and powerful solvent that will dissolve most aromatic and unsaturated hydrocarbons, organic nitrogen
compounds, organo-sulfur compounds and many inorganic salts. It is miscible with most of the common organic solvents such as
alcohols, esters, ketones, lower ethers, chlorinated solvents and aromatics. However, saturated aliphatic hydrocarbons are virtually
insoluble in DMSO.
As a reaction solvent, DMSO is valuable for displacement, elimination, and condensation reactions involving anions. In DMSO, the
rates of these reactions are often increased by several orders of magnitude. In free radical polymerizations , higher average molecular
weights have been reported when DMSO was used as the reaction solvent.
The dominant characteristics of DMSO most important in its usefulness as a reaction solvent are its high polarity, its essentially
aprotic nature, and its solvating ability toward cations. The high dipole moment of the sulfur-oxygen bond (4.3) and the high dielectric
constant (approx. 48) for bulk DMSO suggest the solvating properties and ability to disperse charged solutes. DMSO is not a
hydrogen donor in hydrogen bonding and poorly solvates anions except by dipolar association to polarizable anions. The hydrogen
atoms of DMSO are quite inert, although they are replaceable under sufficiently severe conditions (bulk pKa = 35.1). The oxygen of
DMSO is somewhat basic and participates strongly as a hydrogen bond acceptor. DMSO forms isolatable salts with several strong
acids.
Owing to its chemical and physical properties, DMSO can be efficiently recovered from aqueous solutions. Commercial users of
DMSO employ a variety of processing schemes in their recovery systems. All of these are based on evaporation or fractional
distillation because of simplicity of design and operation. Unlike some other solvents, DMSO can be easily separated from water by
distillation in substantially pure form. For example, DMSO containing less that 500 ppm water can be recovered from a solution
containing 50 weight percent water with only 15 column plates at a reflux ratio of 1:1.
Dimethyl sulfoxide occurs widely in nature at levels of 3 ppm or less. It has been found in spearmint oil, corn, barley, malt, alfalfa,
beets, cabbage, cucumber, oats, onions, swiss chard, tomatoes, raspberries, beer, coffee, milk and tea. DMSO is a common
constituent of natural waters. It has been identified in seawater in the zone of light penetration where it may represent an end product
of algal metabolism. Its occurrence in rainwater may result from oxidation of atmospheric dimethyl sulfide which in turn occurs as part
of the natural transfer of sulfur of biological origin.
No attempt has been made in this bulletin to present a complete literature survey of all the uses of DMSO as a reaction solvent,
solvent, or reactant. A few carefully chosen references have been selected to illustrate the most important areas of DMSO chemistry.
For persons wishing to learn more about DMSO as a reaction solvent, ir any other information in this bulletin, please write or call:
P.O. Box 1209
Slidell, LA 70459-1201
(985) 649-5464
5
PART I. PROPERTIES OF DMSO
TABLE I. Physical Properties of DMSO
Reference
Molecular Weight
Boiling Point at 760 mm Hg
78.13
189 °C (372°F)
(342)
Freezing point
18.45°C (65.4°F)
(342)
Molal freezing point constant, °C/(mol)(kg)
4.07
(2151)
Refractive index nD25
1.4768
(581)
Surface tension at 20°C
Vapor pressure, at 25°C
43.53 dynes/cm
0.600 mmHg
(2223)
(372)
Density, g/cm3, at 25°C
1.099
(581)
Viscosity, cP, at 25°C
2.0 (see Figs. 3 & 4)
(581)
Specific heat at 29.5°C
0.47+/- 0.015 cal/g/°C
(3215)
Heat capacity (liq.), 25°C
0.47 cal/g/°C
(2900)
Heat capacity (ideal gas)
Cp(T°K)=6.94+5.6x10 –2T-0.227x10-4T2
(353)
Heat of fusion
41.3 cal/g
(232)
Heat of vaporization at 70°C
Heat of solution in water at 25°C
11.3 kcal/mol (260 BTU/lb)
Heat of combustion
-54 cal/g, @ ∞ dilution
6054 cal/g; (473 kcal/mole)
Flash point (open cup)
Auto ignition temperature in air
95°C (203°F)
300-302°C (572-575°F)
Flammability limits in air
lower (100°C)
3-3.5% by volume
upper
(3215)
(342)
42-63% by volume
Coefficient of expansion
0.00088/°C
(342)
Dielectric constant, 10MHz
48.9 (20°C)
(342)
45.5 (40°C)
Solubility parameter
Dispersion 9.0
(8070)
Polar 8.0
H-bonding 5.0
Dipole moment, D
4.3
(342)
Conductivity, 20°C
3x108(ohm –1cm -1)
(342)
80°C
7x108(ohm –1cm -1)
PKa
35.1
(10411)
Thermal and Chemical Stability of DMSO
As shown in Figure 5, DMSO is highly stable at temperatures below 150° C. For example, holding DMSO at 150° C for 24 hours, one
could expect a loss of between 0.1 and 1.0%. Retention times even in batch stills are usually considerably less than this, and
therefore, losses would be correspondingly less.. It has been reported that only 3.7% of volatile materials are produced during 72
hours at the boiling point (189° C) of DMSO (1). Slightly more decomposition, however, can be expected with the industrial grade
material. Thus, about 5% DMSO decomposes at reflux after 24 hours (3921). Almost half of the weight of the volatile materials is
paraformaldehyde. Dimethyl sulfide, dimethyl disulfide, bis(methylthio)methane and water are other volatile products. A small amount
of dimethyl sulfone can also be found. The following sequence of reactions explains the formation of these decomposition
products (1):
H3CSOCH3
H3CSH + HCHO
(HCHO)x
2H3CSH + HCHO
2H3CSH + CH3 SOCH3
2H3 CSOCH3
(H3 CS) 2CH2 + H2O
H3 CSSCH 3 + H3 CSCH3 + H2 O
H3CSO 2CH3 + H2 CSCH3
6
DMSO is remarkably stable in the presence of most neutral or basic salts and bases (3922). When samples of DMSO (300g) are
refluxed for 24 hours with 100g each of sodium hydroxide, sodium carbonate, sodium chloride, sodium cyanide, sodium acetate and
sodium sulfate, little or no decomposition takes place in most cases. The results are shown in Table II below (3922):
7
FREEZING POINT CURVES FOR DMSO-WATER SOLUTIONS
8
TABLE II
Results of Reflux of DMSO for 24 Hours with Various Compounds
Compound (1008)
in 300 g DMSO
Reflux
Temp.,° C.
DMSO Recovered
% of Original
DMS (a)
NaOH
Na2CO3
NaCI
NaCN
NaOAc
Na2SO4
DMSO only
185-140e
190
190
148-164f
182-187
181-148g
189
93.7
96.3
98.7
100.0
97.0
85.4
98.0
63
31
14
15
22
66
15
33
8
30
30
% of Decomposition Products,
DMDS(b)
BMTM(c)
HCHO
M Md
20
11
(a) Dimethyl sulfide
(b) Dimethyl disulfide
(c) Bis(methylthio)methane
(d) Methyl mercaptan
(e) Reflux temp. decreased from 185°C to 140°C over the first 16 hours.
(f) Reflux temp. was 148°C for 20 hours; increased to 164° C during the last 4 hours.
(g) Reflux temp. decreased gradually from 181°C to 148° C.
DMSO does not seem to be hydrolyzed by water and very little decomposition of DMSO takes place when it is heated under reflux for
periods of 5 to 16 hours. The following tests, shown in Table III, have been performed: 1)10 parts DMSO + 1 part water, 2) 60 parts DMSO
+ 5 parts water + 1 part sodium hydroxide, 3) 60 parts DMSO + 12 parts water + 1 part sodium bicarbonate, 4) DMSO alone (3922):
Composition of Sample,
Parts
10 DMSO:1 H 2 O
TABLE III
Refluxing of DMSO and Mixtures For Shorter Periods
Reflux
Time
DMSO Organic Product Composition,
Time,°C.
Hr.
100
DMS
DMDS
152
5
0
0
15
99.7
0.15
0
60 DMSO:5 H 2 O:1 NaOH
155
60 DMSO:12 H 2O:1 NaHCO3
131
DMSO only
191
5
8
6
12
5
9
16
99.8
99.3
99.9
99.8
99.8
99.1
99.0
0.1
0.6
0.1
0.2
0.1
0.2
0.2
0.1
0.1
0
0
0.1
0.2
0.2
BMTM
0
0.15
0
0
0
0
0
0.5
0.6
9
DMSO is also stable in the presence of concentrated sulfuric or hydrochloric acid at 100° C for up to 120 minutes of heating at atmospheric
pressure. Phosphoric acid causes more rapid decomposition of DMSO than does sulfuric or hydrochloric acid. Detected decomposition
products are dimethyl sulfide, dimethyl disulfide, and, in smaller quantity, formaldehyde. The results are shown in Table IV (3920):
TABLE IV
Effect of Heating DMSO with Concentrated Acids - (200g DMSO with 20g of concn. acid)
Acid
Conc.
H2SO4
36N
Temp.,
° C.
100
H2SO4
36N
125
H3 P04
85%
100
H3 P04
85%
125
HCI
12N
95
HCI
12N
115
Time,
Min.
DMSO Left,
%
% of
Decomposition Products
15
99
DMS(a)
100
30
120
- 15
150
210
15
30
45
60
120
150
15
60
150
15
30
60
120
15
30
45
60
120
99
98
86
86
80
92
89
89
87
87
86
84
82
82
99
99
99
98
93
92
87
87
87
100
100
7
7
10
25
45
45
46
46
50
25
33
33
100
100
100
100
100
100
100
100
100
DMDS (b)
93
93
90
75
55
55
54
54
50
75
67
67
HCHO
some
some
(a) Dimethyl Sulfide
(b) Dimethyl Disulfide
10
11
FIGURE 6
Recovery from Aqueous Solutions
Many chemical processes using DMSO require the addition of water to stop the reaction or to separate the product from the solvent
(DMSO). DMSO can be separated efficiently and cleanly from this water and other impurities by distillation. DMSO distillations are not
complicated by any known azeotropes.
A typical feed to a recovery operation is relatively weak in DMSO - 10 to 20%. There would usually be two vacuum distillation steps in
the recovery:
1) Evaporation of the DMSO-water solution overhead to eliminate less volatile impurities, if any are present, and
2) Fractional distillation of the DMSO-water solution to recover pure DMSO.
Recovery may be done batchwise or continuously, employing moderate conditions. An operating pressure of about
100 mm Hg abs. would allow the use of 85 psig steam and normally available cooling water.
PART II
SOLVENCY CHARACTERISTICS OF DMSO
The solvent characteristics of DMSO derive mainly from its being highly polar and aprotic. Because of its high polarity it forms
association bonds with other polar and polarizable molecules, including itself. Thus, it is miscible with water and almost all types of
organic liquids except the saturated alkanes. It has a high solvency for the large organic molecules containing polar groups. DMSO has
also exhibited an ability to dissolve many inorganic salts, particularly those of the transition metals or those which have nitrates,
cyanides or dichromates as their anions.
12
The following tables of solubilities are offered as a guide and an easy reference.
Solubility of salts ----------- -----------------------------------------------------------------------------------------Table V
Solubility of resins and polymers ---------------------------------------------------------------------------------Table V I
Solubility of miscellaneous materials ---------------------------------------------------------------------------Table VII
Solubility of gases -------------------------------------------------------------------------------------------------- Table VIII
The difficulty of predicting solubility characteristics suggests that each specific compound be checked for its solubility in DMSO rather
then generalizing from reported solubilities. Because of the variability of resins and polymers from one manufacturer to another,
tradenames and companies have been used to identify accurately the materials in Table VI.
The study of co-solvent possibilities utilizing DMSO has not been included as the complexity and diversity of this field are too broad to
give adequate coverage. It will be noted however from Table VII that DMSO is compatible with most of the common solvents. This
compatibility and the strong solvency properties of DMSO indicate numerous possibilities for co-solvent systems to perform given tasks
efficiently and economically.
TABLE V
Solubility of Salts in DMSO (794)
Solubility Grams/100 cc DMSO
Solubility Grams/100 cc DMSO
25°C.
90-100°C.
25°C.
90-100°C
Aluminum sulfate (18H 2O)
Insol.
5
Lithium dichromate (2 H 2O)
10
Ammonium borate (3H2O)
10
Lithium nitrate
10
Ammonium carbonate (H2O)
1
Magnesium chloride (6 H 2O)
1
Ammonium chloride
Insol.
10
Magnesium nitrate (6 H 2O)
40
Ammonium chromate
1
Manganous chloride (4 H 2O)
20
Ammonium dichromate
50
Mercuric acetate
100
Ammonium nitrate
80
Mercuric bromide
90
Ammonium thiocyanate
30
Mercuric iodide
100
Barium nitrate
1
Molybdenum bromide
1
Reacts
Beryllium nitrate (4 H 2O)
10
Nickel chloride (6 H 2O)
60
Bismuth trichloride
1
Nickel nitrate (6 H 2O)
60
Cadmium chloride
20
Potassium iodide
20
20
Cadmium iodide
30
Potassium nitrate
10
Calcium chloride
Insol.
1
Potassium nitrite
2
Calcium dichromate (3 H 2O)
50
Potassium thiocyanate
20
50
Calcium nitrate (4 H 2O) 2
30
Silver nitrate
130
180
Ceric ammonium nitrate
1
Sodium dichromate (2 H 2O)
10
Cobaltous chloride (6 H 2O)
30
Misc. m.p. 86°C. Sodium iodide
30
Cupric acetate (H2O)
Insol.
6
Sodium nitrate
20
Cupric bromide
1
20 150°C.
Sodium nitrite
20
Cupric chloride (2 H 2O)
Insol.
27
Sodium thiocyanate
1
Cuprous iodide
1
Stannous chloride (2 H 2O)
40
Ferric ammonium sulfate (12 H 2O) Insol.
Misc. m.p. 40° C. Strontium bromide (6 H 2O)
5
Ferric chloride (6 H 2O)
30
90
Strontium chloride (2 H 2O)
10
Ferrous chloride (4 H 2O)
30
90
Tungsten hexachloride
5
Gold chloride
5
Uranyl nitrate (6 H 2O)
30
Lead chloride
10
Vanadium chloride
1
Lead nitrate
20
60
Zinc chloride
30
60
Zinc nitrate (6 H 2O)
55
-
13
TABLE VI
Solubility of Resins and Polymers in DMSO
Grams Soluble in 100 cc DMSO
90-100°C
Comments
Material
Polyacrylics
Orlon (du Pont)
Acrilan (Monsanto)
Verel (Eastman)
20-30°C
Creslan (Am. Cyanamid)
Zefran (DOW)
Polyamides
Nylon 6
Nylon 6/6
Nylon 6/10
Cellulose
Cellulose triacetate
Viscose rayon
Cellophane
Carboxymethyl cellulose
Epoxies
Epon 1001 (Shell)
Epon 1004 (Shell)
Epon 1007 (Shell)
Methacrylates
Lucite 41, 45 (du Pont)
Plexiglass (Rohm & Haas)
Polycarbonates
Lexan (General Electric)
Merlon (Mobay)
Polyesters
Dacron (du Pont)
CX 1037 (Goodyear)
Atlac (ICI-America)
Silicones
Dow Corning 803 soln.
Dow Corning 805 soln.
Dow Corning “Sylkyd 50”
Dow Corning Z6018 (flake)
Urethanes
Vithan (Goodyear)
Vinyls – Polymers & Co-polymers
Butvar B-76 (Monsanto)
Formvar 7/70 E (Montsanto)
Elvanol 51-05 (du Pont)
Elvanol 52-22 (du Pont)
Elvanol 71-24 (du Pont)
Polyvinyl pyrrolidone (GAF)
Geon 101 (PVC Goodrich)
Vinylite VYHH (Union Carbide)
Teslar (du Pont)
5
-
Insol.
-
Insol.
Insol.
Insol.
10
-
20
<1
Insol.
Insol.
50
50
50
-
-
<1
<1
-
>5
Insol.
-
>1
7
50
Miscible
Miscible
Miscible
70
-
-
100
30
2
-
20
42
90
15
30
>100
10
30
-
>25
>5
20
-
Viscous soln.
25 at 130°C with some
decompostion
25 at 130°C
40 at 150°C
25 at 150°C
40 at 150°C
Dissolves at 160°C ppts.
130°C
Very viscous
Very viscous
Viscous
Viscous
Viscous
Partially sol. at 160-170°C
14
Vinylidenes
Darvan (Goodrich)
Saran film (Dow)
Geon 200 x 20 (Goodrich)
DNA (Goodrich)
Other Resinous Materials
Melmac 405 (Am. Cyanamid)
Neoprene
Polyethylene
Polystyrene
Rosin (Hercules)
Penton (chlorinated polyether)
(Hercules)
Teflon (du Pont)
Vinsol (Hercules)
5
>5
30
20
-
70
Insol.
Insol.
>100
Insol.
Insol.
-
Insol.
50
5
Insol.
>100
Soln. Cloudy and viscous
25 at 130°C
Sol. At 150°C ppts at 130°C
TABLE VII
Solubility of Miscellaneous Materials in DMSO
Material
Solubility
Grams/100 cc DMSO
20-30°C
90-100°C
Acetic acid
Acetone
Acrawax
Acrawax B
Aniline
Beeswax
Benzene
Benzidine
Benzidine methane sulfonate
Bromine
Miscible
Miscible
<1
Insol.
Miscible
Miscible
Soluble
Insol.
Reacts
>1
4
<1
-
Butenes
Clacium methyl sulfonate
Camphor
Candelilla wax
Carbon
Carbon disulfide
Carbon tetrachloride
Carbowax 600
Carbowax 6000
Carnauba wax
Castor oil
Ceresin wax
Chlorine
Chloroform
Chlorosulfonic acid
Citric acid
Coconut oil
2.1
Soluble
Soluble
Insol.
90
Miscible
Miscible
Insol.
Miscible
Reacts
Miscible
Reacts
>70
0.3
Soluble
<1
8
<1
<1
1.3
Misc.-160°C
Softens
100
-
Cork
Cresylic acid
Cumene
Cyclohexane
Cyclohexylamine
Decalin
n-Decane
Di-n-butylamine
o-Dichlorobenzene
p-Dichlorobenzene
Dicholorodiphenyltrichloroethane
Dicyandiamide
Dicyclohexylamine
Diethylamine
Diethyl ether
bis-(2-ethylhexyl)amine
Diethyl sulfide
Di-isobutyl carbinol
Softens
Miscible
Miscible
4.67
Miscible
4.5
0.7
11
Miscible
Very Soluble
4
40
4.5
Miscible
Miscible
Miscible
0.7
Miscible
Material
Glycerine
Glycine
Hexane
Hy-wax 120
Iodine
Isoprene
Kerosene
Lanolin, hydrated (Lanette O)
Lauryl amide (Amid 12)
Lorol 5
Lubricating oil
Methionine
Methyl borate
Methyl caprate
Methyl iodide
Methyl laurate
Methyl mercaptan
N-methyl morpholine
Methyl palmitate
Methyl salicylate
Methyl sulfonic acid
Methylene chloride
Microcrystalline wax
Morpholine
Naphthalene
Neoprene
Nitrobenzene
Oleic acid
Ouricuri wax
Oxalic acid
Paint (dried)
Palmitic acid
Paraffin
Paraformaldehyde
Pentaerythritol
n-Pentane
Pentene 1 & 2
Perchloric acid
Petroleum ether
Phenol
Phosphoric acid
Phosphorus trichloride
Phthalic acid
Isophthalic acid
Terephthalic acid
Picric acid
Solubility
Grams/100 cc DMSO
20-30°C
90-100°C
Miscible
<0.05
0.1
2.9
<1
Soluble
Miscible
0.05 (0.5% DMSO soluble in 11 (gets cold)
10
>20
Miscible
0.4
0.1
0.3
Miscible
Miscible
Miscible
Reacts
7
Miscible
40
Miscible
Immiscible
Misc. 130-180°
Miscible
Miscible
Miscible
<1
Miscible
Miscible40
Insol.
Insol.
Miscible
Miscible
1
38
Softens & dissolves
100
Insoluble
Insoluble
Slightly soluble
5-10
30
0.35
7.1
Reacts violently
3 (DMSO soluble 0.3-0.5% in petroleum
ether)
Soluble
Miscible
Reacts vigorously
90
68
76
26
33
Soluble
-
15
Di-isobutylene
Dimethyl ether
Dimethyl formamide
Dimethyl sulfide
Dimethyl sulfone
Dioxane
Diphenyl
Dipentene
n-Dodecane
Dodecylbenzene (Neolene 400)
Dyes
Burnt Sugar
FD&C Blue
Pistachio Green B
Ethyl benzoate
Ethyl alcohol
Ethyl bromide
Ethyl ether
Ethylene dichloride
Formalin (37%)
Formamide
Formic Acid
3.3 (0.6% DMSO soluble in
di-isobutylene)
4.4
Miscible
Miscible
33.9
Miscible
Miscible
Very Soluble
10
0.38
3.5
Soluble
Soluble
Soluble
Miscible
Miscible
Miscible
Reacts
Miscible
Miscible
Miscible
Miscible
Miscible
-
Pyridine
Pyrogallol
Rosin
Rosin soap
(Hercules Dresinate X)
Sevin
Shellac, white, dried
Silicon tetrachloride
Sodium
Sorbitan sesquioleate
Sorbitan trioleate
Sorbitol
Soybean oil
Starch, soluble
Stearic acid
Succinic acid
Sugar (sucrose)
Sulfamic acid
Sulfur
Sulfuric acid
Tallow
Tallow amide, hydrogenated
(Armour Armide HT)
Tetrahydrophthalic anhydride
Thiourea
Toluene
Toluene di-isocyanate
Tributylamine
Tricresyl phosphate
Triethanolamine laurylsulfate
Triethanolamine
Triethylamine
Trinitrotoluene
Turpentine
Urea
Water
Xylene
Miscible
-
50
>100
Slightly soluble
0.9
50
Reacts vigorously
2.5
60
0.6
>2
2
30
30
40
Miscible
Insol.
80
Reacts
Miscible
>180
Miscible
100
<1
1.9
Insol.
>40
50
40
Miscible
Miscible
0.9
Miscible
Soluble
Miscible
10
Soluble
10
40
Miscible
Miscible
85
110
-
TABLE VIII
Solubility of Gases in DMSO at Atmospheric Pressure and 20°C
(from pure gases in each case)
Grams Gas per
100 Grams Solution
Acetylene
Ammonia
Butadiene
Mixed butylenes
Carbon dioxide
Carbon monoxide
Ethylene
Ethylene oxide
Freon 12
Helium
Hydrogen
Hydrogen sulfide
Isobutylene
Methane
Nitric oxide (NO)
Nitrogen
Nitrogen dioxide (NO2, N2O4)
Oxygen
Ozone
Sulfur dioxide
2.99
2.6
4.35
2.05
0.5
0.01
0.32
60.0
1.8
Insol.
0.00
0.5 (reacts)
2.5-3.0
0.00
0.00
0.00
Miscible (possible reaction)
0.01
Reacts
57.4 (reacts)
Gas Volume per
Volume of DMSO
28.1
40.0
3.0
2.8
306.0
3.7
0.06
16
PART III
REACTIONS OF DMSO
1. Oxidation of DMSO
DMSO reacts with strong oxidizing agents to give dimethyl sulfone, CH3SO2CH . Ozone gives a good yield of the sulfone (825)(8923).
Both dichromate oxidation (321) and permanganate oxidation (9222) have been used for quantitative determination of DMSO (1612).
Aqueous chlorine under acidic conditions gives dimethyl sulfone and
methanesulfonyl chloride (1273)(8548), but under alkaline conditions the oxidation is accompanied by chlorination to give an 80% yield
of hexachlorodimethyl sulfone (905):
CH3SOCH3 + NaOCl
CCl3SO2CCl3
Sodium hypobromite similarly gives a 75% yield of hexabromodimethyl sulfone (229). DMSO reacts with hydrogen peroxide (10224),
organic peroxides (1515), or hydroperoxides (8105), particularly in the presence of catalysts (4136), to give the sulfone. It has been
reported that the persulfate ion can remove an electron from the sulfur of DMSO to give a radical cation, which is a suitable
polymerization catalyst for acrylonitrile (1271). DMSO is also oxidized by peroxydiphosphate (9563) and chloramine-T (9678).
2. Reduction of DMSO
DMSO is reduced to dimethyl sulfide, CH SCH , by a number of s trong reducing agents, including aluminum hydrides (1024)(1022)
and boranes (1138)(3429)(3816)(8885). Mercaptans reduce acidified DMSO and are oxidized to the disulfides
(428)(1373)(2532)(2779)(8054)(8095)(8405)(9949):
acid
2RSH + CH 3SOCH 3
RSSR + CH3SCH 3 + H2O
3. Reaction with Metals
The reaction of DMSO with sodium and potassium metals does not lead to simple removal of a hydrogen, but occurs by cleaving the
carbon-sulfur bond (206):
CH 3SOCH 3 + 2M
CH3SOCH3 + CH3 -M+
CH 3SO -M+ + CH 3 -M+
CH 3SOCH 2- M+ + CH 4
The electrolytic reduction of sodium chloride or sodium iodide in DMSO similarly leads to a mixture of hydrogen and methane gases at the
cathode (1508).
4. Reaction with Strong Bases - Dimsyl Ion
Methylsulfinyl carbanion, dimsyl ion, H 2CSOCH3.
The activating influence of the sulfinyl group on a-hydrogens is considerably less than that of a carbonyl group but
still sufficient to give a pKa of 35.1 for DMSO (10411). Consequently, strong bases such as sodium hydride or sodium amide react with
DMSO to produce solutions of sodium methylsulfinyl carbanion (dimsyl ion) which have proved to be synthetically useful (634):
CH3 SOCH3 + NaH
+ NaCH2SOCH3 + H2
As the base, the dimsyl sodium solution can be employed to remove protons from carbohydrates, amines, amides, acetylenes, weakly
acidic hydrocarbons and many other compounds. The dimsyl ion has also been used to prepare salts of carbonyl compounds, and for
eliminations producing olefins, aromatics and cyclopropane derivatives. There are numerous applications of the dimsyl ion in the
isomerization of alkynes and formation of phosphorus ylides in preparing Wittig reagents.
The dimsyl ion solutions provide a strongly basic reagent for generating other carbanions. The dimsyl ion shows the expected
nucleophilicity of carbanions and serves as a source of methylsulfinylmethyl groups (634).
Thus, with alkyl halides or sulfonate esters, sulfoxides are obtained; carbonyl compounds yield ß-hydroxysulfoxides and esters give ßketosulfoxides (624):
n-C4H9Br + :CH 2SOCH3
(C6H5) 2CO + :CH2SOCH3
C6H5COOEt + :CH2SOCH3
n-C4H9CH2SOCH3
(C6H5) 2C(OH)CH2SOCH3
C6H5C(O)CH2SOCH3
Zinc and sulfuric acid have been used to reduce DMSO (86). Quantitative procedures for determining DMSO have been based on its
reduction using stannous chloride and hydrochloric acid (982), or titanium trichloride in dilute hydrochloric acid (272). DMSO is
reduced only very slowly with hypophosphorus acid unless catalyzed by dialkyl selenides (1005). Hydroiodic acid reduces DMSO
(7073), and the kinetics of the reaction have been examined (84)(85)(1687)(1544). Hydrogen bromide, on the other hand, reduces
DMSO only at temperatures about 80° C (1579). DMSO has also been reduced with iodine-sulfur dioxide or bromine-sulfur dioxide
complexes (9464), cyclic phosphoranes derived from catechol (9944), silanes (10085)(10127), thiophosphoryl bromide (10139) and
other reagents. Quantitative or almost quantitative yields of dimethyl sulfide are claimed in some of these reductions.
The dimsyl ion also adds to carbon-carbon double bonds, and if the mixture is heated for several hours, the initial adduct eliminates
methanesulfenic acid. The overall result is m ethylation and with compounds such as quinoline or isoquinoline, yields are nearly
quantitative (202):
17
H 2CSOCH3
N
N
N
isoquinoline
H
CH2SOCH3
CH3
Care is required in running these reactions because the decomposition of the intermediate sulfoxide anion (and also dimsyl sodium)
during the heating in the strongly alkaline system is exothermic and also produces a precipitate which can interfere with heat removal.
Explosions have been observed which were not detonations but were due to a pressure build-up by an uncontrolled exotherm (8).
5. Reaction with Acid Halides
DMSO has long been known to react with chlorine or acid chlorides, such as sulfur monochloride, S2Cl2, to give chloromethyl methyl
sulfide, whereas with sulfuryl chloride, SO2Cl2, only 13% of the chloromethyl methyl sulfide is obtained (720). Aromatic sulfonyl chlorides
(463), thionyl chloride (595), and organic acid chlorides also give chloromethyl methyl sulfide (467)(8601). With thionyl chloride, it has
been suggested that the reaction, in a simplified form, can be represented as follows:
CH3SOCH3 + SOCl 2
CH3SCH 2Cl + SO 2 + HCl
The reaction in many cases proceeds by way of initial attack of the chlorinating agent upon the oxygen of DMSO, followed by removal of
a proton to give an ylide which is finally attacked by chlorine (459):
+ [(CH3 )2 SOMZ] X
CH SOCH + Z-M-X
3
3
-
-
X (e.g. Cl )
-
[CH2 SOCH2:]
OMZ + CH 3SCH2 X
M-Z +HX
M= an atom (such as S) to which the halogen atom X is attached
Z=the remaining portion of the molecule
The kinetics of the reaction between DMSO and acetyl chloride has been studied using NMR spectroscopy. The decay of DMSO and
acetyl chloride follows mainly 2nd order kinetics. The growth of the main products, acetic acid and chloromethyl methyl sulfide is mainly
second order. The overall reaction is complicated by several side reactions, which generate acetoxymethyl methyl sulfide, acetic
anhydride and chlorodimethylsulfonium chloride (9773):
CH3SOCH3
OCH3CCl
CH3SCH2Cl + CH3CO2H + (CH3CO) 2O +CIS(CH3)2 +Cl-
This displacement of a reactive chloride by the DMSO oxygen has been used to introduce hydroxyl groups into compounds that are
sensitive toward water (459)(294)(1016)(1383)(3152). Thus, DMSO reacts with cyanuric chloride to give cyanuric acid and with benzoyl
chloride to give benzoic acid, (1383):
N 3C3Cl + 3CH3SOCH 3
PhCOCl + CH3SOCH3
N 3C3O 3H3 + 3CH 3SCH2Cl
PhCO 2H + CH 3SCH 2Cl
The ability of suIfoxides to react with acid chlorides can be used for the quantitative determination of DMSO. When DMSO is reacted with
acetyl chloride in the presence of iodide the following reaction, involving formation of the acyloxysulfonium salt, can be represented as
follows:
CH3SOCH3 + CH3COCl
+
[(CH 3)2SOCOCH 3] + 2l
[(CH 3) 2SOCOCH 3]+ + ClCH 3SCH 3 + l 2 + CH 3CO2
The iodine is then titrated with sodium thiosulfate (1805).
The reaction of DMSO with reactive acid chlorides is vigorous and exothermic and should be conducted with care (669)(8601)(10470).
6. Reaction with Acid Anhydrides
Carboxylic acid anhydrides react with DMSO in a manner similar to that of acid halides. With acetic anhydride, the final product is
acetoxymethyl methyl sulfide, CH3CO2CH2SCH3 (290)(291). Several mechanisms of the reaction, the Pummerer rearrangement, have
been proposed. There seems to be little doubt that the first step in the reaction of DMSO with acetic anhydride is the formation of the
acetoxysulfonium salt (2643)(2896). Various possible pathways of the rearrangement from the sulfonium salt have been proposed, but
18
the one going through the ylide seems likely (2643)(4820). The Pummerer rearrangement can then be represented by the following
reactions
O
O
O
CH 3SOCH 3 +
CH 3
S
(CH 3CO)2O
O
CH3
H3 C
O
O
H3 C
O
H 3CS
CH2
O
S
CH3
CH3
CH2
+CH3CO2 H
O
CH 3
H 3CSH 2 CO
CH 3
DMSO also reacts with trifluoroacetic anhydride to give the acetoxysulfonium salt. When this intermediate is reacted with aromatic
amines, amides or sulfonamides the corresponding iminosulfuranes are obtained (7044). When aliphatic carboxylic acids are treated
with DMSO activated by tert-butylbromide in the presence of NaHCO3 the corresponding methylthiomethyl esters are obtained in a
Pummerer like reaction (10032). A Pummerer type rearrangement is also suggested in the reaction of diphenylphosphinic anhydrideDMSO reaction (4128):
O
[Ph 2PO]2O
+
CH 3SOCH 3
+
P
Ph
Ph2PO2H
OCH 2SCH 3
Ph
Inorganic anhydrides also attack the DMSO oxygen. The sulfur trioxide-DMSO complex reacts easily with cellulose to give cellulose
sulfate esters with a high degree of substitution (1474).
Reactions of DMSO wlth some acid anhydrides, both organic and lnorganic, can be vigorous and should be conducted with care. Thus,
acetic anhydride and benzoic anhydride react with DMSO even at room temperature (290), although higher temperatures, e.g. 85-90° C,
are needed for faster reactions (7613).
Complex formation between DMSO and sulfur trioxide is an exothermic reaction. To avoid overheating with consequent darkening and
violent boiling of the mixture, sulfur trioxide should be added slowly to a cool well stirred and cooled DMSO (1474).
DMSO cannot be dried with phosphorus pentoxide because this may lead to an explosive mixture (354).
7. Halogenation of DMSO
DMSO can be halogenated with chlorine or bromine in the presence of a base. Thus, stirring a solution of DMSO, pyridine, and
bromine in chloroform results in the formation of bromomethyl methyl sulfoxide (3148):
Br2, pyridine, CCl4
CH3SOCH3
0oC
CH3SOCH2Br
48%
3 hr.
Similarly, bubbling chlorine into a DMSO, pyridine and methylene chloride solution at 0° C for over 30 minutes produces chloromethyl
methyl sulfoxide in a 77% yield (6268).
Chlorination of DMSO in the presence of triethylamine yields chloromethyl methyl sulfoxide. Further chlorination in the presence of
pyridine yields methyl trichloromethyl sulfoxide (4802):
CH3 SOCH3
Cl2 , Et3 N, CCl4
o
-5 to 5 C
Cl2 , pyridine, CHCl3
CH3SOCH2Cl
60%
below 5 oC
CH3SOCCl3
30%
3 hrs.
Bromination of DMSO with elemental bromine leads to the formation of trimethylsulfonium bromide. Methanesulfonic acid,
paraformaldehyde, dimethyl disulfide, and hydrogen bromide are formed as by-products (4802):
Br 2
+
CH 3 SOCH 3
(C H 3 ) 3 S B r
o
2 0 -5 0 C
7 5%
A small amount of hydrogen halides or halogens, especially bromine or hydrogen bromide, catalyze the decomposition of DMSO in the
absence of a base. This catalytic decomposition takes place sluggishly. The reaction of bromine proceeds via the initial a-bromination to
afford a-bromethyl methyl sulfoxide which is oxidized (Kornblum reaction) to afford the products listed above [(4802)]. These consecutive
reactions form an oxidation-reduction cycle between Br2-HBr and DMSO-dimethyl sulfide (8400).
8. Reaction with Phenols and Aniline
19
a) Acid chloride or hydrogen chloride catalysis.
When a solution of phenol in DMSO is treated with an acid chloride, such as thionyl chloride, or saturated with hydrogen chloride, the
initially formed adduct of DMSO reacts by electrophilic attack on the phenol to form the sulfonium salt. The sulfonium salt can be
decomposed by heating to give hydroxyaryl methylthioethers (2075)(302)(296):
OH
+
OH
+
Cl
CH3SCH 3
CH 3SOCH 3 + HCl
Phenol
heat
S(CH 3) 2 Cl-
OH
SCH 3 + CH3Cl
+
R
4-(methylthio)phenol
Up to 60% yields are obtained, depending on the structure of the phenol. p-Hydroxyaryl methylthioethers are also obtained when phenols
are suspended in 70% perchloric acid and DMSO is added, followed by heating of sulfonium salts in hot, saturated potassium chloride
solution (1268):
OH
ClO-4H2O, KCl-
HClO 4
+ CH3SOCH3
OH
S(CH3)2
+
15-20o C
2-3 hours
OH
SCH3
reflux
4-5 hrs.
65-68% R
R
R
Similarly, hydroxyaryl thioethers can be prepared by reacting phenols with DMSO in sulfuric acid, and heating the crude reaction mixture
with aqueous sodium chloride (6335) (6674)(6613).
N,N-dimethylaniline can be reacted with DMSO using phosphoryl chloride catalysis. However, the yield of the aryl thioether is lower in
this case (348). Other aromatic amines and hydrazine derivatives also react with DMSO and dicyclohexylcarbodiimide (4651).
b) Dicyclohexylcarbodiimide or acid anhydride catalysis
The reaction of phenols with DMSO and dicyclohexylcarbodiimide in the presence of phosphoric acid or pyridinium trifluoroacetate
affords a mixture of the products consisting mainly of 2-methylthiomethyl phenol and 2,6-bis(methylthiomethyl)phenol
(540)(1234)(4898)(4891). It has been suggested that the mechanism proceeds according to the following steps (540)(1234)(4898):
H
CH 2SOCH 3 + H+ + C 6H11-N=C=N-C 6H 11
+
C 6H11-N-C=N-C 6 H5
O
S(CH 3)2
phenol
O
+
(CH 3)2SO
O
CH3
S
- CH
2
H
+
base
C
H
N
N
C6 H11
C 6H11
OH
O
H
Ch 2SCH 3
H3 CSCh 2
2-thiomethoxymethyl phenol
A similar reaction takes place when acetic anhydride (849)(1055) or the pyridine-sulfur trioxide complex (4636) is used to polarize
the DMSO molecule instead of dicyclohexylcarbodiimide.
Finally, it has been found that phenols can be methylthiomethylated by boiling with excess DMSO. A mixture of isomeric
methylthiomethylation products are obtained, but o-methylthiomethylation is preferred (4636)(4772).
9. Alcohol Oxidation with DMSO
A breakthrough in the preparation of carbonyl compounds from alcohols has been achieved with the development of reagents based on
20
DMSO (8551)(1503)(4820)(16359).
Several procedures have been developed which permit the selective oxidation of structurally diverse primary are secondary alcohols to
the corresponding carbonyl compounds, i.e. aldehydes and ketones, respectively. Most of these reactions take place at room
temperature or above. Nucleophilic attack occurs on the DMSO sulfur atom. Most reactions in which the nucleophilic attack takes place
on sulfur are aided by prior electrophilic attack on the oxygen atom (10720):
O
O
CH3SCH3 + E
+
E
CH3SCH3
+
The electrophilic reagents which activate DMSO include acetic anhydride, trifluoroacetic anhydride, and other acid anhydrides, the sulfur
trioxide-pyridine complex, thionyl chloride, oxalyl chloride, acetyl chloride, and other, acid chlorides, bromine, chlorine, t-butyl
hypochlorite, dicyclohexylcarbodiimide, and others.
The labile intermediate, the DMSO-electrophile complex, can now be attacked by a nucleophile, such as an alcohol, to perform a
displacement on sulfur with oxygen as the departing group:
E
Nu
O
S
H3C
+ Nu
H 3C
CH3
+ OE-
S
CH 3
Several of the above-mentioned activating agents and their use in the oxidation of alcohols are described below.
a) Acetic anhydride
In this procedure an alcohol is treated with a mixture of acetic anhydride and DMSO at room temperature (1127) (9926). DMSO first
reacts with acetic anhydride to form the acyloxysulfonium salt which in turn reacts with the alcohol to give the alkoxydimethylsulfonium
intermediate which decomposes to the carbonyl compound and dimethyl sulfide (DMS)(1127):
CH3 SCH3 + (CH3CO)2 O
[(CH3)2S-O-COCH3] +CH3COOacyloxysulfonium salt
CH3SCH3 + RR'C=O
[(CH3) 2S-O-CHRR']++CH3 COO-
A number of side reactions take place when using the acetic anhydride-DMSO procedure. The usual side products are acetates and
methylthiomethyl ethers, RR'CHOCH2SCH3. The advantage of the acetic anhydride-DMSO method is the fact that highly hindered
alcohols , which would be inert to other DMSO-activator systems, are oxidized (4820).
b) Trifluoroacetic anhydride
Trifluoroacetic anhydride and DMSO react exothermally at -60° C. in methylene chloride to produce a white precipitate, presumably an
ion pair, trifluoroacetoxydimethylsulfonium trifluoroacetate.
+
[(CH3)2S-O-COCF3]-OCOCF3
This reacts rapidly with alcohols, even sterically hindered ones (e.g. 2-adamantol and neopentyl-type alcohols) to give the
corresponding carbonyls (7943)(8455). Trifluoroacetic anhydride is an excellent activator for DMSO because of short reaction times and
high yields of carbonyl compounds with minimal by-product formation. The major drawback is the need to work at very low temperatures
(-30 to -60° C) (10720).
c) Dicyclohexylcarbodiimide
This method of oxidation is generally referred to as the "Pfitzner-Moffatt" technique, after its originators (1503). The reaction involves
addition of an alcohol substrate to a solution of dicyclohexylcarbodiimide (DCC) in DMSO with an acid, such as phosphoric acid or
pyridinium trifluoroacetate (172), present as a proton source. This results in reaction conditions near neutrality at room temperature. The
oxidation technique is applicable to primary or secondary alcohol groups in an almost unlimited variety of compounds, including
alkaloids, steroids (173), and carbohydrates (4349). Steric effects are not important except in highly hindered systems (1503). In the
reaction, the DMSO molecule is first converted to a labile intermediate which is susceptible to attack at the sulfur by an alcohol group to
produce an alkoxysulfonium salt which undergoes base-catalyzed decomposition to the carbonyl compound (3049):
21
C6 H11 HN
C6H11 -N=C=N-C6H11 + H+OS(CH 3)2
C
N
C 6H11
HOHCRR'
O
CH 3SCH 3
O
H
+
(CH3)2S-O-CRR'
C6H11
C6H11
N
H
N
H
alkoxysulfonium salt
H
-H+
R'
O
O
SH
+
(CH3)2S-O-CRR'
CH 3
+ CH3SCH3
R H
R
R'
:CH2
Protecting groups such as isopropylidene, benzylidene, acetate, benzoate, and sulfonate esters and ethers are stable in the conditions
used for oxidation (3602)(175).
d) Phosphorus pentoxide
It has been found that DMSO containing phosphorus pentoxide rapidly oxidizes the alcoholic groups of carbohydrates and other
compounds at room or elevated temperatures to the corresponding aldehydes or ketones (208). In general, oxidations proceed most
efficiently in the presence of 3-4 molar equivalents of DMSO and 1.2-2.0 molar equivalents of phosphorus pentoxide (2327). The
carbohydrate oxidation with DMSO-P4O10 should be run at about 60-65°C. This system catalyzes carbohydrate polymerization at
temperatures below 35° C (5296) (6079). DMSO, DMF and pyridine seem to be the best solvents for this reaction (3602)(2327)(6691).
e) Sulfur trioxide-pyridine
The combination of DMSO with S03-pyridine complex in the presence of triethylamine yields a reagent that rapidly oxidizes primary and
secondary alcohols in good yield at room temperature to aldehydes and ketones, respectively (9926)(10720). An attractive feature of this
reagent is its property of effecting oxidation of allylic alcohols to the corresponding a , ß-unsaturated carbonyl compounds (1752).
The S03-pyridine complex in DMSO can be used to oxidize acid-labile trans -diols (4037) or cis -diols (8033) to quinones. This reagent has
also been used to oxidize alkaloid hydroxyl groups to ketone groups (2749)(8017). Application of the DMSO-S03-pyridine reagent to
partially acetylated carbohydrates leads to oxidation as well as elimination of the elements of acetic acid, thus providing a high yield to
novel unsaturated carbohydrates (2652):
OHC
O
R3 = H
OR 1
OAc
OR 2
SO3, DMSO R1=H
R3OH2C
R3 OH2 C
O
O
OAc
OR
1
O
OAc
OAc
2
OR
CH2
O
2
OR
R =H
OAc
O
22
f) Oxalyl chloride
Oxalyl chloride is an efficient and useful activator, superior to trifluoroacetic anhydride, for the conversion of alcohols to their
alkoxysulfonium salts which, upon basification, result in generally higher and frequently quantitative yields of the corresponding carbonyl
compounds (9786)(9926). The unstable intermediate formed at low temperatures (usually-60° C) instantaneously loses carbon dioxide
and carbon monoxide. The new intermediate is the same as that proposed for the dim ethyl sulfide-chlorine reagent. This product has been
reacted with a wide variety of alcohols to convert them to the carbonyl compounds (10084):
CH2Cl2-60o
CH3SOCH3 + (COCl)2
+
[(CH 3)2S-Cl] Cl-
O
O
C
C
-CO2, -CO
[(CH 3)2S
O
RR'CHOH
Cl] Cl
(Et) 3N
[(CH3) 2SOCHRR'] Cl
RR'C=O + CH2SCH3
10. Kornblum Reaction
Kornblum and co-workers have demonstrated that in DMSO a -bromoketones at room temperature and primary alkyl tosylates on heating
afford the corresponding carbonyl compounds, presumably through an oxysulfonium intermediate (273)(8551):
+
[(CH3)2S-O-CHRR']X
CH3SOCH3 + XCHRR'
B:
+
RR'C=O + BH
Some reactive alkyl halides, such as methyl iodide, also react with DMSO to form the oxosulfonium intermediate (the O-alkyl derivative).
However, this intermediate rearranges readily to the more stable oxosulfonium salt, i.e. (CH3)3S+Ol-, and no oxidation takes place (324).
Some reactive halides, such as benzyl, can also be oxidized to the corresponding carbonyl compounds but higher reaction temperatures
are necessary. An acid acceptor, e.g. sodium hydrogen carbonate, is frequently used (105).
The relatively unreactive alkyl halides, such as 1 -chloroheptane, can be oxidized by DMSO if the chloride is first converted to the tosylate
(106).
The DMSO oxidation of the primary allylic chloride, 4-chloro-3-methyl-2-buten-1-ol acetate, does not proceed well when sodium hydrogen
carbonate is used as the acid acceptor. However, this reaction runs well when a dibasic metal phosphate, Na2HPO4 or K2HPO4, is used
(9960):
CH 3
CH 3
DMSO
H 2CCl
C
CHCH 2OCOCH
OHC
3
CHCH 2OCOCH3
C
o
M2HPO4, 80 C
This particular reaction is catalyzed by sodium bromide (9960)(10066).
11. Methoxydimethylsulfonium Salts and Trimethyloxosulfonium Salts
Alkylating agents, such as methyl iodide, react initially with DMSO at the oxygen to give methoxydimethylsulfonium iodide (see the
previous section, Kornblum Reaction). These alkoxysulfonium salts are quite reactive and with continued heating either decompose to
give the carbonyl compounds or rearrange to the more stable trimethyloxosulfonium salts. In the case of methyl iodide
trimethylsoxosulfonium iodide is produced (324):
(CH3)2SO + CH3I
-
[(CH3)2SOCH3]+I-
[(CH3)3SO]+I
methoxydimethylsulfonium
iodide
trimethyloxosulfonium
iodide
Trimethyloxosulfonium iodide is of interest because treatment with sodium hydride or dimsyl sodium produces dimethyloxosulfonium
methylide which is an excellent reagent for introducing a methylene group into a variety of structures (632)(2463)(4820):
O
[(CH3) 3SO]+ I- + NaH
(CH 3) 2S
CH 2 + NaI + H2
dimethyloxosulfonium
methylide
Many aldehydes and ketones react with the ylide to give better than 75% yields of epoxides (632):
H
C
O
(CH3)2S
CH2 +C6H5CH=CHC(O)C6H5
(C 6H5)2C
CH2 + (CH 3)2SO
90 % yield
In a similar case, the dimethyloxosulfonium methylide reacts with carbon-carbon double bonds that are conjugated with carbonyl groups to
give cyclopropane derivatives (4820)(7361):
23
H2
C
O
(CH3)2S
CH2 +C6H 5CH=CHC(O)C6 H5
C 6H5 CH
CHC(O)C6H 5
PART IV. DMSO AS A REACTION SOLVENT
A. DISPLACEMENT REACTIONS IN DMSO
These are reactions in which reactive groups are replaced by nucleophilic ions or molecules.
The largest category of reactions in which DMSO has been used as a solvent is that in which labile groups are replaced by nucleophilic
ions or molecules. The reason for the particular utility of DMSO in these reactions has not always been established and derives from a
number of factors. DMSO as one of the most polar of the common aprotic solvents. It is a favored solvent for displacement reactions
because of its high dielectric constant and because anions are less solvated in it (9488). The high dielectric constant of a solvent insures
that dissolving species or a solute bearing opposite charges do not come together to agglomerate. E.g. when sodium hydroxide is
dissolved in DMSO, the interaction between Na' and OH- is minimized. Due to the polarity of the sulfoxide bond and the electron density at
the oxygen, cations are much more solvated by DMSO than the anions. Conversely, the aprotic nature of DMSO precludes the solvation of
anions by hydrogen bonding so that these are solvated only by dipolar attraction and thereby are more reactive. In other cases, the
controlling influence is suggested to the ability of highly polar DMSO molecules to stabilize transition state structures and thereby lower the
activation energy (22) (471)(399). This latter effect is evident in the cases where comparatively minor additions of DMSO cause significant
enhancement of reaction rates (1262).
A great variety of displacement reactions can be run in DMSO and suitable nucleophiles include:
1. Acetylide ion
10. Cyanide ion
2. Alkoxide ion
11. Halogen ion
3. Amides
12. Hydroxide ion
4. Amines
13. Mercaptide (or Thiophenoxide) ion
5. Ammonia
14. Nitrite ion
6. Azide ion
15. Phenoxide ion
7. Carbanions
16. Sulfide (or Hydrosulfide) and Thiosulfate ions
8. Carboxylate ion
17. Thiocyanate ion
9. Cyanate ion
1. Acetylide Ion
The usual reactions of sodium acetylide may be accomplished in good yield by stirring a slurry of sodium acetylide in DMSO slightly below
room temperature with reagents such as alkyl halides, epoxides or carbonyl compounds (544). Displacement of halides with the ethylenediamine complex of lithium acetylide is also easily effected in DMSO (3178)(4175). Thus, the reaction of 1-bromo-5-chloropentane with
lithium acetylide-ethylene diamine complex in DMSO gives 7-chloro-1 -heptyne (1826):
Cl(CH2) 5Br +
HC
DMSO
CLi+
Cl(CH2) 5C
CH
The use of lithium acetylide-ethylene diamine in DMSO has given higher yields of the desired products than sodium acetylide in liquid
ammonia (4175).
The addition of lithium acetylide as the ethylene-diamine complex to 7-bromoheptanol tetrahydropyranyl ether in DMSO gives non-8-yn-1ol tetrahydropyranyl ether in higher than 90% yield (4333).
2. Alkoxide Ion
The high activity of alkoxide ions in DMSO shows up in their enhanced basicity. The basicity of alkoxides reaches a maximum in DMSO
when the mixture is substantially free of hydroxylic material. In this case, the acidity of the alcohols in dilute solutions is about 103 times
that of DMSO so that only a minor equilibrium quantity of the DMSO anion is present (734). The reactivity of the alkoxide ion in DMSO is
influenced by the cation and is greater with cesium and with lithium less (606)(1162). The vastly enhanced activity of alkoxide ions in
DMSO over their activity in alcohols is attributed to the absence of alkoxide-solvent hydrogen bonds in DMSO which are present in the
hydroxylic solvents (434).
The basicity of alkoxides in DMSO is conveniently expressed n terms of acidity functions, and a number of these are plotted in Figure 10
for bases n DMSO-water and DMSO-methanol systems.
Alkoxides differ in their solubilities n DMSO. Thus, potassium t-butoxide is more soluble than some lower alkoxides (17). The solubilities
of these hydroxylic bases are also shown in Table IX for comparative purposes.
A review article on potassium t-butoxide and its use in nucleophilic displacements has been published (6815).
TABLE IX Solubilities of Various Bases in DMSO
Substance
moles/liter
Reference
24
NaOH
7.6 x 10'°
(725)
KOH
1 x 10'3
(17)
(CH ) NOH
1 x 10'
(17)
NaOCH3
1.6 x 10'3
(725)
NaOEt
2 x 10'2
(17)
iso-PrONa
7 x 10'3
(17)
n-BuONa
5 x 10'3
(17)
t-BuOK
1 x 10'2
(17)
a) Aliphatic halide displacement
The rate of reaction of alkoxide ions with alkyl halides in alcohol-DMSO mixtures to form ethers increases with the increasing amount of
DMSO. This is illustrated in the reaction of methyl iodide with methoxide ion or with ethoxide ion to make dimethyl- or methyl ethyl ethers,
respectively (329), and in the reaction between benzyl chlorides and methoxide ion to make the corresponding benzyl methyl ethers
(433). The rate increase at high DMSO concentrations is attributed to an increased activity of the methoxide ion caused by reduced
solvation, but other factors are probably more important at low DMSO concentrations. The activation energy decreases continuously as
the DMSO concentration increases (433). The Williamson ether synthesis from alcohols and alkyl halides (chlorides) with sodium
hydroxide as the base can be considerably improved by using DMSO as the solvent in place of the excess alcohol (2924):
NaOH, DMSO
ROR'
ROH + CIR'
100oC
6-14 hrs.
Secondary alkyl chlorides and primary alkyl bromides give little etherification, elimination being the major reaction.
The use of alkoxides in DMSO in some cases involves elimination n addition to displacement, followed by the addition of the alkoxide to
the double bond in alicyclic compounds (1798).
b) Aromatic halide displacement
As with alkyl halides, the use of alkoxides in DMSO can involve both the displacement and elimination reactions with aromatic halogen
compounds. Thus, when a solution of 3-bromo-tropolone in DMSO is heated with sodium methoxide, an almost 1:1 mixture of 3methoxytropolone and 4-methoxytropolone is obtained in 96% yield (3572):
Br
OCH3
O
O
O
OH
O-
OH
O
+
NaOCH3, DMSO
NaOCH3, DMSO
H3CO
3-methoxy
tropolone
benzyne-type
intermediate
OH
4-methoxy
tropolone
Aromatic halogens in nitroaryl halides can be displaced by the methoxide ion in DMSO-methanol. The reaction rate increases some
1000-fold when the DMSO concentration is increased to 80% (399):
NO2
F
-
DMSO
k1
O-
+ OR
+
N
O
OR
DMSO
k2
NO2
OR
F
R = C2H5 or t-Bu
p-Nitrochlorobenzene also reacts with alkoxides. When 2-alkylamino-ethanol is first treated with dimsyl sodium to make the oxyanion
base followed by the addition of p-nitrochlorobenzene, the preferential nucleophilic attack by oxygen (rather than the amino group) is
insured (8399):
+
NaH2CSOCH 3, DMSO
Cl
RHN(H2C)2O
RHN(CH2)2OH +
NO2
NO2
The reaction of monoiodo-, monobromo-, monochloro- and monofluoro-naphthalenes with potassium butoxide in butyl alcohol-DMSO
has been examined (4058)(4059). The major products observed in the bromo-, iodo- and chloronaphthalene reactions are 1- and 2-butyl
naphthyl ethers, 1- and 2-naphthols and 1-methylmercapto-2naphthol. This suggests that 1,2-dehydrohaphthalene is an intermediate in
each of these reactions, and 1-methyl-mercapto-2-naphthol is probably the benzyne intermediate-DMSO reaction product (4059). The
25
fluoronaphthalenes undergo only direct nucleophilic substitution with no formation of 1,2-dehydronaphthalene, i.e. no benzyne-type
intermediate (4058)(5244):
OH
O
F
t-BuOK-DMSO
+ t-BuOK
+
70 oC
14 hours
27%
38%
(degradation
product of the ether)
2,3-Dichloranisole can be prepared by reacting 1,2,3-trichlorobenzene with sodium methoxide in DMSOmethanol (9107).
The kinetics of the reaction of 2-bromo-, 2-bromo-3-methyl-, and 2-bromo-5-methylpyridine and methoxide ion in DMSO containing small
amounts of methanol have been determined (2125). The ortho:para ratio is higher at lower temperatures (2.5 at 40° C vs 1.44 at 110* C):
OCH3
R'
R'
R
R'
R
R
DMSO
+
+ -OCH3
40-110 oC
N
N
Br
N
OCH3
2-Bromopyridine reacts with potassium methoxide in DMSO containing 1 % of methanol 3000 times faster than it does with the same
reagent in pure methanol at 110°C.
A number of 4-alkoxypyridines is prepared by reacting 4-chloropyridine with sodium alkoxides in DMSO in moderate to high yields
(5038).
5-Bromo-3-methyl-4-nitroisothiazole reacts smoothly with sodium alkoxides in alcohols -DMSO to give the appropriate 5-alkoxy-3 -methyl4-nitroisothiazoles (4098):
CH 3
NO2
DMSO
CH3
NO2
+ NaOR
60-100oC
N
S
N
Br
S
OR
c) Nitro group displacement
When sodium methoxide or sodium ethoxide is added to p-nitro- or p,p'-dinitrobenzophenone in DMSO, almost quantitative yields of palkoxy- or p,p'-dialkoxybenzophenone are obtained (470):
O
O
NO2
ROH-DMSO
OR
NO2 +NaOR
C
C
OR
o
20 C
24 hrs.
Sulfonamides are also alkylated in DMSO.4,6-Dichloropyrimidine reacts with the sodium salt of p-nitrobenzenesulfonamide in DMSO to
give 4-chloro-6-(p-nitrobenzenesulfonamido)pyrimidine (42):
With 2,2'-dibromo-4,4'-dinitrobenzophenone, there is no displacement of bromide ion, and 2,2'-dibromo-4,4'dimethoxybenzophenone
(90%) is obtained. No reaction occurs in any instance when dioxane is used instead of DMSO (470).
d) Sulfinate displacement
When ß-styrylsulfones are treated with one molar equivalent of sodium alkoxides in DMSO, ß-alkoxystyrenes are formed by
nucleophilic substitution (9761):
iv
CH=C OR
CH=C SO Ph
2
R'"
R
R"
R'
iv
DMSO
R'"
NaOR
room temp.
R
R"
R'
10-68%
e) Sulfonate displacement
Benzene sulfonates of common primary and secondary alcohols react rapidly with sodium methoxide in DMSO to give high yields of alkyl
methyl ethers and/or alkenes. The ether-alkene ratio is significantly higher in reactions with sodium methoxide than with potassium tbutoxidesulfonyl ester groups from carbohydrate derivatives, the conversion to the ether with sodium methoxide or sodium e. More olefins
are formed from secondary sulfonate esters than from primary esters (580)(592). In the displacement of methane thoxide in DMSO occurs
by the attack on the sulfur, leading to the retention of configuration, rather than by the usual attack on carbon with inversion (1119)(653).
3. Amides
26
The N-alkylation of amides can take place in DMSO. The reaction of various ? -haloamides with the dimsyl ion in DMSO can be used to
obtain good to high yields of 4-, 5- and 6-membered lactams. However, the reaction with dimsyl ion fails to produce the seven-membered
heterocyclic ring (888):
H
O
N
C
H 2CSOCH 3 , DMSO
(CH 2 )n Br
X
N
(CH 2 )n
X
O
X = Br, Cl, F, I;
N = 2, 3, 4
The readily available base, dimsyl ion, could be more convenient to work with than sodium in liquid ammonia (888). The alkylation of the
sodium salt of saccharin with a benzyl chloride also proceeds well in DMSO to give a high yield of N-benzyl saccharin (947):
7-Oxo-7,8-dihydro-s-triazolo[4,3-a]pyrimidine can be alkylated as above using p-chlorobenzyl chloride in DMSO. In this case, however a
mixture of the N-benzyl- and the O-benzyl deriviatives results (3885):
H
O
H
R
N
O
N
+ RCl
N
N
O
N
N
N
NaOH, DMSO
N
N +
N
N
N
R =CH2
Cl
It has been found that the N-alkylation of carboxylic acid amides proceeds well in DMSO by using dry potassium hydroxide as the base.
Good yields can be obtained even at room temperature (4355):
O
O
KOH, DMSO
54-90%
+ R"X
R
RT
NHR'
R
NR'R"
With DMSO as the solvent, the use of stronger bases, such as sodium hydride or potassium alkoxides, is not necessary.
When the sodium salt of an acetamidonitrile in DMSO is treated with chloramine, a smooth N-amination is achieved (4382):
CN
CN
DMSO
+ ClNH2
NNa
H3CO
NNH2
H3COC
H3CO
H3COC
OCH 3
OCH3
Peptides and proteins can also be N-alkylated with methyl iodide and benzyl bromide using DMSO as the solvent and the dimsyl ion as
the base (4945).
A number of amides, such as acetanilide, have been N-alkylated with dialkyl sulfates using potassium hydroxide as the base and DMSO
as the solvent (8276):
O
KOH, DMSO
NHCCH 3 +
(RO) 2SO 2
20 oC
R
O
N
CCH 3
The sodium salt of an amide can displace a methoxy group from a benzene nucleus. Thus, the treatment of 2-acetamido-2'methoxybenzophenone with sodium hydride in DMSO gives the 9-acridone (8564):
O
O
NaH, DMSO
NH OCH3
COCH 3
room temp
N
COCH3
68%
27
4. Amines
In most displacement reactions, the nucleophiles are negatively charged. However, displacements can also take place involving
uncharged nucleophiles, namely, amines (3433). Amines, like ammonia, do not hydrolyze DMSO. The presence of DMSO in the
displacement reaction involving amines allows the reagents to surmount the energy barrier easier than in hydroxylic solvents, irrespective
of the charge type of the reagents. The effect of DMSO, then, must be the decrease in- the energy of the transition state. It could also be
said that DMSO polarizes a substrate (399). For a reaction involving neutral reactants, such as amines, and going through a charged
transition state, it appears that DMSO can solvate the cationic part of the reacting system at the point of attack of the amine reagent
(1240). Thus, displacement reactions by amines in DMSO generally proceed at a good rate. A catalytic effect is seen by adding DMSO to
an alcohol system containing amines and aryl halides (399)(1262).
a) Aliphatic halide displacement-primary amines
Alkylation of weak aromatic amines with alkyl bromides (e.g. 2-aminofluorenone with ethyl bromide) in DMSO gives ring brominated Nalkyl derivatives (211). However, aralkylation of 2-aminofluorenone with aralkyl bromide, such as benzyl- and para-substituted benzyl
bromides in DMSO leads to azomethines as the main products (264):
Br
+ BrH 2 C
X
DMSO
o
100 C
1.5 hrs
HC
X
N
O
NH2
O
DMSO also catalyzes the reaction between 2-substituted carboxylic acids and amines. Thus, ethylenediamine reacts with chloroacetic
acid to give ethylenediaminetetraacetic acid (EDTA) (4910):
H2NCH2CH2NH2 + 4ClCH2CO2H
DMSO
(HO2CCH2)2NCH 2CH2N(CH2CO2H) 2
o
80 C
b) Aliphatic halide displacement-secondary amines
? -Bromoalkylbenzofuranones react with morpholine in DMSO to give high yields of the N-alkylation products (613):
O
O
O
O
DM SO
(CH2)nBr +NH
(CH2)n
O
N-
O
Ph
Ph
yield almost quantitive if n=1 or 2
n=1,2,3,4
The morpholinoethylbenzofuranone is formed by direct halogen displacement and no rearrangement reactions take place.
c) Aliphatic halide displacement-tertiary amines
The reaction between triethylamine and ethyl iodine has been investigated in benzene, DMSO and various benzene-DMSO mixtures.
The reaction rate increases with increasing DMSO concentration in the solvent. Although DMSO reacts slowly with alkylating agents,
quaternizations, such as the reaction of triethylamine and ethyl iodide, proceed much more rapidly to give a high yield of
tetraethylammonium iodide (585):
DMSO
(C2H5)3N + C2H5I
(C2H5)4N+I-
20-50oC
Similarly, when p-nitrocumyl chloride is treated with quinuclidine in DMSO, a 90% yield of pure quaternary ammonium chloride can be
isolated (3433):
(CH3)2
C
Cl
(CH3 )2
DM SO
+
N
O2
C
Cl +
N
N
room temperature
10 hours
N
O2
90%
28
d) Aromatic halide displacement - primary amines
A series of primary amines has been reacted with 4-nitrofluorobenzene in DMSO to determine the rate constants. DMSO was selected as
the solvent because of its relatively high boiling point and the fact that most nucleophilic reactions in DMSO proceed at a fast rate (1638).
These reactions are run in the presence of an excess of amines:
DMSO
NO2
F
+
NHR + RNH 3F-
NO2
+ 2RHN2
Similarly, benzylamine reacts with 2,4-dinitrochlorobenzene (399):
DMSO
C6H5CH2NH 2 + CIC 6H3(NO 2) 2
C6H5CH2NHC 6H3(NO 2)2
e) Aromatic halide displacement - secondary amines
The displacement of aromatic halides by secondary amines in DMSO has been studied rather extensively. The fluoro compounds undergo
substitution by various nucleophiles, such as secondary aliphatic and alicyclic amines, at rates 100 to 1000 times faster than their chloro
analogs. The rate of displacement of fluorine is further enhanced by the order of 103 to 105 in dipolar aprotic solvents, such as DMSO, as
compared with reactions in aprotic solvents (471). Thus, 4-fluoroacetophenone undergoes a very rapid displacement of the halogen by
amines, such as morpholine, in DMSO and affords in high yields the corresponding 4-amino derivatives, which are otherwise difficult to
prepare (398):
DM SO
OCCH3
+
X
NH
OCCH3
N
X = F, Cl, Br
The yields of products obtained in DMSO are higher than those obtained with DMF under comparable conditions.
The reaction of 2,4-dinitrochlorobenzene with piperidine, which is known to be insensitive to base catalysis, is nevertheless accelerated by
DMSO (538).
The rate constants for the reaction of 4-nitrofluorobenzene in DMSO with 19 secondary amines have also been determined. This reaction
is the fastest with pyrrolidine, azacyclobutane and dimethylamine, and slowest with methylanisidine, diisobutylamine and diethanolamine
(1639).
The dechlorination of 2- and 4-chloroquinolines, as well as 6- and 8-alkyl-substituted 4-chloroquinolines with piperidine in DMSO and
other solvents has been studied (1240)(1239)(1238).
f) Nitro group displacement
In some cases, activated nitro groups can be displaced by amines. Thus, 2,5-dinitro-1 -methylpyrrole undergoes nucleophilic aromatic
substitution by piperidine (7756):
NO2
O2 N
DMSO
+
N
O2N
NH
N
N
CH3
CH3
The reaction with the amine is favored by the accelerating effect of DMSO in aromatic substitutions by neutral nucleophiles.
g) Alkoxide and phenoxide displacement
The reaction of n-butylamine or t-butylamine with 2,4-dinitro-1 -naphthyl ethyl ether gives the corresponding 2,4-dinitro-1 naphthylamines in high yields (3445):
OC 2 H5
NHR
NO2
NO2
DMSO
+
RNH2
room temp
NO2
NO2
1-Piperidino-2,4-dinitronaphthalene can be prepared by reacting 1-methoxy-2,4-dinitronaphthalene with piperidine in DMSO. 1 Dimethylamino-2,4-dinitronaphthalene is prepared similarly (8408). The kinetics of the reaction of piperidine, n-butylamine, morpholine
and benzylamine with 2,4-dinitrophenyl phenyl ether in DMSO has been studied as a function of amine concentration. The reactions of
29
the secondary amines are base catalyzed; those of the primary amines are not (9138).
5. Ammonia
DMSO is stable to ammonia. Displacement reactions with ammonia and amines are examples where the nucleophile is uncharged
(3433). The solubility of ammonia is 40 liters per liter of DMSO at 1 atmosphere or 2.6% by weight (5033).
a) Aliphatic halide displacement
Reaction of methyl 2-bromo-3-phenyl-3-butenoate with ammonia in DMSO gives the desired a-amino ester (10134):
DMSO
Ph
C
CHCO2 CH3 + NH3
CH2
Ph
room temp.
1.5 hrs.
Br
C
CHCO2CH3
CH2
NH2
88%
Secondary amine by-products are not found in any significant amounts in the above reaction. Somewhat similarly, isopropyl 2,3-dibromo2,3-dihydrocinnamate reacts with ammonia to give isopropyl 2-phenyl 3-aziridine-carboxylate (10143):
DMSO
PhCHCHCO2CH(CH3)2 + NH3
PhCHCHCO2CH(CH3)2
room temp.
3 hours
Br Br
N
H
High yields of nitrilotriacetic acid are claimed when ammonia is reacted with chloroacetic acid in DMSO (4910):
N(CH2CO2H)3 + 3NH 4Cl
4NH3 + 3ClCH2 CO2 H
b) Aromatic halide displacement
2,4-Dinitrochlorobenzene reacts with ammonia to give 2,4-dinitroaniline (402):
Cl
NH 2
NO2
NO 2
DMSO
+ NH3 (aq.)
room temp.
several hrs.
NO 2
NO 2
93%
Similarly, p-aminotrifluoroacetophenone reacts with ammonia in DMSO (3399):
O
O
DMSO
F + NH3
F3 CC
NH2
135oC.
24 hrs.
F3 CC
42%
When DMF is
used as the solvent in the above
reaction, p-dimethylaminotrifluoroacetophenone results, apparently due to the hydrolysis of DMF to dimethylamine:
O
O
F
+ NH 3+(H3 C)2 NCHO
(NCH 3 )2
F3CC
F3CC
c) Alkoxide displacement
Displacement of an -OMe group by ammonia produces 3-amino-2-heteroarylpropenenitriles (10458):
Ar
C
CN
CHOCH3 + NH 3
Ar
DMSO
C
CH-NH2
CN
84-95%
6. Azide Ion
Rate constants for displacement reactions by the azide ion in DMSO are up to about 10,000 times greater than for the same reaction in
protic solvents, such as methanol (471). Reactions are frequently run with an excess solid sodium azide, making it a pseudo first-order
30
process. Under these conditions, the rate is also a function of the solubility of the reagent. Measurements of solubility show that sodium
azide is much more soluble in DMSO than in some other solvents, and the solubility increases slightly with the addition of water (7527).
TABLE X
__________________________________Solubility of Sodium Azide in Four Solvents______________________
Solubility, mol/l.
Dry
1% H 2O
5% H2O
10% H2O
______________ (110°)
(110°)
(110°)_________
2-Methoxyethanol
0.31 (124°)
DMF
0.10-0.12
0.17
0.28
0.48 (25-150°)
DMSO
1.5-1.6
1.6
1.8
1.9 (95-150°)
HMPA
0.43
0.45
0.48
0.51 (110-150°)
a) Aliphatic halide displacement
Some aliphatic halides are easily displaced by the azide ion in DMSO (4815). Thus, the reaction of 2-(2nitrophenyl)ethyl bromide with a
3-fold excess of sodium azide gives a 95% yield of 2-(2-nitrophenyl)ethyl azide (4360):
CH2CH2 N3
CH2CH2 Br
DM SO
+ NaN3
NO2
NO2
b) Aromatic halide displacement
Treatment of 4-fluoro- or 4-iodonitrobenzene with sodium azide in DMSO produces a quantitative yield of 4-nitrophenyl azide (471):
DMSO
NO2
X
+ NaN3
NO2
N3
o
100 C.
100 %
X = F or I
When 4-chloro-3-nitrobenzoic acid is treated with sodium azide in DMSO, the 5-carboxybenzofuroxan results (1007):
CO 2H
CO2H
DMSO
+ NaN3
N+
NO 2
N
Cl
O-
O
Reaction of 2-chloroquinoxzline 1-oxide with sodium azide in DMSO at room temperature gives 2-azidoquinoxaline (9767):
N
N
DMSO
+ NaN3
N
O
N
O
52%
Cl
N3
c) Nitro group displacement
The aromatic nitro group can also be displaced by dry sodium azide in DMSO (6572). Thus, 2,3-dinitroacetanilide with sodium azide
gives the monoazido-derivative (4600):
HNOAc
HNOAc
NO 2
N3
DMSO
+ NaN3
NO 2
o
90 C
NO2
87%
d) Sulfonate displacement
Sulfonates, such as toluenesuIfonates and methanesuIfonates are also readily displaced by the azide ion in DMSO (4920)(8339). A high
yield of the 2,3-diazidobutane is obtained when meso-1,4-di-0-acetyl-2,3-di-0-(methylsulfonyl)erythrol is reacted with a slight excess of
sodium azide (7692):
OMes
OMes
N3
DMSO
N3
+ 2 NaN3
31
60-100oC
OAc
OAc
OAc
OAc
The above described displacements are frequently used to prepare amino sugar derivatives by reducing the azido to the corresponding
amino group (5481)(7071).
e) Other displacements
Treatment of fumaronitrile with sodium azide in DMSO with subsequent acidification leads to 1,2,3-triazole-4-carbonitrile (4249):
CN
DMSO
NC
+ N3
CN
[NC
CH
CH
N3 ]
C
CH
N
N
N
H
7. Carbanions
The majority of carbanions which are usually prepared as reaction intermediates or as transistory species in chemical reactions are
readily obtained in DMSO.
a) Aliphatic halide displacement
The alkylations of 2,4-pentanedione with alkyl iodides and sodium hydride as the base may be more conveniently and rapidly achieved
when DMSO is used in place of the usual alcohols or non-polar solvents (4261):
O
CH3
C
H2
C
O
NaH, DMSO
C
CCH 3 + 2RX
CH 3
R
O
C
CCH 3
R
X= I or Br
Similar results are obtained with malononitrile (599).
Alkylation of malonic esters in DMSO can be faster than in DMF, dimethoxyethane, THF and benzene. This alkylation is strongly
accelerated by comparatively minor additions of DMSO to benzene. This could mean that DMSO disperses the ion aggregates
(611)(612).
With ambient anions where either carbon or oxygen alkylation is possible, DMSO favors oxygen alkylation (690):
O
O
+ PhCH2Br DMSO
O
Ph
95%
This is also demonstrated in the alkylation of ß -ketoesters, where a proper choice of alkylating agent, temperature, and alkali metal can
lead to significant amounts of O-alkylation (773)(1114)(1229).
Interaction of the potassium salt of 2-carbethoxy-cyclopentanone with an alkyl halide in DMSO at room temperature provides good yields
of alkylated keto esters and probably constitutes the best method of alkylating this ß-ketoester (1823):
O
O
DMSO
CO2C2H5
room temperature
78%
6 hrs.
CO2C2H5+
Br
K+
b) Aromatic halide displacement
Substituted o-nitrohalobenzenes reaction DMSO in the presence of powdered KOH with deoxybenzoin to form the corresponding
nitroarylated deoxybenzoins (9439):
O
Cl
NO2
R +
Ph
O
KOH, DMSO
Ph
Ph
Ph
NO2
R
32
c) Nitro and sulfinate group displacement
It has been discovered that aliphatic nitro and sulfone groups can be displaced at tertiary carbon. Thus, the treatment of a,-pdinitrocumene with the lithium salt of 2-nitropropane in DMSO gives the alkylation product (1237):
NO 2
NO 2
+
Li CH3
+ H C
3
NO 2
DMSO
71%
o
25 C
NO 2
NO 2
Nitrobenzenes substituted by an electron withdrawing group, such as p-dinitrobenzene, readily undergo displacement by the lithium salt of
2-nitropropane in DMSO (8436):
NO2
NO 2
+
Li+
H3C
CH3 DMSO
25oC
NO2
75%
NO 2
NO2
The sulfone group of a-nitrosulfones is also easily displaced by carbanions, e.g. the lithium salt of 2-nitropropane or the lithium salt of
nitrocyclohexane (7108):
R'
NO2
R SO2Ar
+
R'
DMSO
R"
Li+ R"
room
temperature
R
"R NO
R"
2
O2N NO2
d) Other displacement reactions
Treatment of 2-cyanomethyl-2’,4’-dimethoxybenzophenone with sodium methoxide in DMSO gives 9-cyano-2-methoxyanthracen-10-ol
(3112):
NC
CN
H3CO
OCH 3
OCH 3
NaOCH3, DMS O
140oC, 10 min.
95%
O
OH
When p-nitrobenzylidene diacetate is reacted with the lithium salt of 2-nitropropane in DMSO, a compound in which one of the acetate
groups is replaced by the C(CH3)2,NO2, group is obtained (7657):
DMSO
O2N
CH(OCOCH 3) 2
+ (CH 3) 2CNO 2
+
Li
O 2N
room temp
3 hrs.
CH(OCOCH 3)2
(CH 3)2
NO2
Treatment of (p-cyanobenzyl)trimethylammonium chloride with the lithium salt of 2-nitroprprane gives the carbon alkylate (10399):
+
CH2N(CH3)3 Cl+
[(CH3)2CNO2}Li+
NC
NO2
DMSO
25 oC
O2N
82%
e) Use of aqueous sodium hydroxide as the base
It has been found that nitriles containing sufficiently activated methylene groups, such as phenylacetonitrile, can be conveniently alkylated
in excellent yields and selectivities by using aqueous sodium hydroxide as the base and DMSO as the reaction solvent (3951):
PhCH2CN +
NaOH(aq), DMSO R
R'X
RX
CN
Ph
Ph R
CN
R'
Previously, these reactions have usually been carried out by treating the nitrile with a strongly basic reagent, such as a metal amide,
hydride, or alcoholate, followed by addition of the appropriate alkyl- or aryl hydride. These latter methods are generally cumbersome and
33
the selectivities are poor (3951).
Similarly, 50% aqueous sodium hydroxide in DMSO can be used as a base to induce an essentially quantitative cyclization of 5-chloro-2pentanone to give cyclopropyl methyl ketone (3398):
O
Cl(H2C)3
O
NaOH (aq), DMSO
CH3
30oC, 15 min
CH3
96%
O- and C-alkylation of benzoins is also easily achieved by the reaction of alkyl halides in aqueous sodium hydroxide in DMSO at ambient
temperatures (4699):
O
O
Ph
RX + Ph
OH NaOH (aq), DMSO
O
Ph
R
OH
Ph
RX
Ph
Ph
R
OR
f) Use of calcium oxide as the base
In some cases, calcium oxide has been used as a base to produce carbanions. Diethyl malonate can be alkylated with benzyl bromide to
yield diethyl benzylmalonate (3931):
H2(CO2C2H5)2
CaO, DMSO
+
63%
CO2C2H5
Cl
C 2H5O2C
The use of lime in the dimethylation of 2,4-pentanedione gives a 73% yield of 3,3-dimethyl-2, 4-pentanedione (3931).
8. Carboxylate Ion
Alkylation of carboxylate ions with alkyl halides in DMSO or DMSO-water is an efficient method of esterification (7950)(365)(8809).
Carboxylate ions have also been used to displace sulfonates (8254). In aqueous DMSO systems, the reaction rate increases as the
concentration of DMSO increases both for intramolecular and intermolecular displacment (407).
a) Aliphatic halide displacement
Simple alkyl halides, such as n-decylbromide, react with disodiurn phthalate in DMSO tog ive, e.g. didecylphthalate in 91 % yield
(2597). Carboxylic acid esters are prepared by reacting an organic halide and potassium or sodium acetate in DMSO (574)(6847).
Carboxylic acid esters are also prepared by reacting an acid with an organic halide in the presence of an alkali metal hydroxide in
DMSO or DMSO-water, e.g. to obtain benzyl acetate (2969):
NaOH
CO 2CH3
+ CH3 CO2H
Cl
DMSO
70-81%
Potassium and sodium methacrylates react in DMSO with xylylene dichlorides in DMSO to give unsaturated, polymerizable
compounds (487):
CH 3
O
CH 3
O
CO 2 Na DMSO
CH 2
Cl
+ 2H2 C
o
140-145 C
CH 3
H 3C
O
nearly quantitative
H 3C
CH 2
Cl
A convenient procedure for preparing pyruvic acid esters utilizes an organic halide as the starting material rather than the
corresponding alcohol (9657). Thus, the reaction of sodium pyruvate with n-octyl iodide or phenacyl bromide in DMSO yields the esters:
O
DMSO
+I(CH2) 7CH3
50oC, 3.5 hrs
CO2Na
O
95%
CO2(CH2)7CH3
34
O
+
Br
CO 2Na
Ph DMSO
50oC, 3.5 hrs
O
O 85%
O
O
Ph
O
A ring opening and displacement reaction takes place when E and Z 2-phenylcyclopropyl bromides react with potassium acetate in
DMSO in the presence of a crown ether (1 8-crown-6) (10465):
R
+ CH3 CO2K
Br
DMSO
o
85 C
R
CHCH 2OCOCH 3
b) Sulfonate displacement
When the sodium or potassium 2-methanesulfonoxybicyclo[3.3.1 ]nonane-1 -carboxylate is heated in DMSO, the corresponding ßlactone is produced (6347):
9. Cyanate Ion
Sodium and potassium cyanates in DMSO can displace reactive halogens (26). When alkyl halides are reacted with cyanates, either
isocyanates or isocyanurates result, depending on the reaction conditions and the solvent (440). DMSO plays a superior role in the
dis placement reaction and also in the subsequent trimerization of isocyanates. These reactions may be written as follows (386):
RX +KCNO
DMSO RNCO + KX
70-80oC an isocyanate.
3 hrs.
O
3RNCO
DMSO
100-150o C
1-2 hours
R
N
N
R
O N O
an isocyanurate
X = Br, I; R = ethyl, n-propyl R
If an organic dihalogen compound is reacted with either potassium cyanate or sodium cyanate, the following reactions take place (9408):
XRX + MNCO
DMSO
XR NCO + MX
70 - 200 o C
R
OCN
NCO +
M= sodium or potassium
X-R-NCO + MCO
MX
Under conditions causing trimerization, the products can be converted to the corresponding cyanurates:
O
O
R
R
R
R
OCN
N
N
NCO
X
N
N
X
or
N
O
O
N
O
O
R
R
OCN
X
10. Cyanide Ion
Perhaps the most widely used of the displaycement reactions in DMSO are those involving the cyanide ion. Halogen atoms and sulfonate
(tosyl) groups are displaced rapidly by cyanide ion. Often the yields of the desired products are higher and side reactions are minimized in
DMSO. Many products are more easily isolated from reaction mixtures containing DMSO.
Certain inorganic cyanides are more soluble in DMSO than in other organic solvents. Thus, DMSO can be used advantageously in
systems where water is undesirable. At 95°C, about 10 g of sodium cyanide and/or 2 g of potassium cyanide will dissolve in 100 cc of
DMSO. At 25°C, 1 g of either is soluble (964)(1924).
The solubility of sodium cyanide in DMSO at various temperatures is shown in Figure 7 below. The solubility of sodium chloride, the usual
inorganic by-product when reacting sodium cyanide with organic chlorine compounds, is illustrated in the phase diagram, Figure 8.
Also soluble in DMSO are mercury cyanide, cadmium cyanide, and mixtures of potassium cyanide with copper, nickel, zinc, cobalt, or
silver cyanides. These mixtures appear to be complex salts (801).
In many cases it is not necessary to have a complete solubility of sodium cyanide in DMSO. Reactions can be run using an agitated,
stirred slurry of sodium cyanide with DMSO. Yields are commonly good with primary aliphatic halides, but somewhat lower with
secondary ones due to dehydrohalogenation (475)(577)(8843).
35
36
a)
Aliphatic halide displacement
The reaction of sodium cyanide with ethyl 6-chlorohexanoate in DMSO gives a high yield of 6-cyanohexanoate (474):
Cl(CH2)5CO2C2H5
+ NaCN
DMSO
CN(CH2)5CO2C2H5
o
95-100 C, 1hr. 90%
+ NaCl
Similarly, ethylene dichloride reacts with sodium cyanide to give acrylonitrile (473):
DMSO
100oC
ClCH 2CH 2Cl + 2 NaCN
H2 C CHCN + HCN + 2NaCl
In the above case, both the displacement and elimination reactions take place.
The use of DMSO allows the cyanide ion to displace halides from neophyl and neopentyl compounds without rearrangement
(475)(7547):
CH 2 Cl
DMSO
1 2 0 o C , 2 4 hr s
+NaCN
26%
ne o p hy l c hlo r id e
The displacement reactions of alkyl chlorides and bromides with potassium cyanide occur much more slowly when compared with
sodium cyanide (475). This could be due to the lower solubility of potassium cyanide in DMSO. The yields are also lower and longer
reaction times are required with DMF, sulfolane and dimethyl sulfolane as solvents (475). It has also been established that both primary
and secondary alkyl chlorides react with sodium cyanide in DMSO to give high yields of the corresponding nitriles in shorter reaction
times than have been obtained with bromides or iodides in aqueous alcohol solvent (577).
When 1-chloro-17-fluoro-8-heptadecyne is reacted with sodium cyanide in DMSO, 1-cyano-17-fluoro-8heptadecyne is produced in high
yield (2189):
DMSO
F(H2C) 8C
C(CH2)7Cl
F(H2C)8C
+ NaCN
o
o
135 -140 C
C(CH2) 7CN
+
NaCl
93.5%
50 min.
The difference in the reactivity of halogens is also illustrated in the reaction of 1,1-dichloro-2-(bromomethyl)-2methylbutane with
potassium cyanide (2769):
Cl 2
Cl 2
Br + KC N DMSO
CN
50%
The use of sodium cyanide in the above reaction gives some undesirable by-products.
The enolate salt of ethyl 4-bromo-3-oxobutyrate reacts with the cyanide ion in DMSO (9135):
CO 2C2H5+ CN- DMSO NC
Br
O
CO 2C 2H5
O 81%
? -Cyano N,N-disubstituted amides are conveniently prepared from halogenated amides by treatment with alkaline cyanides (9985):
R O
R O
Cl
NC
CH3
+ NaCN
CH3
N
N
n
DMSO, 80oC
n
CH3
CH3
Poly[3,3-bis(chloromethyl)oxocyclobutane] reacts with sodium cyanide in DMSO to give the bis(cyanomethyl) derivative (6847):
CH2Cl
O n +
CH2Cl
DMSO
2nNaCN
120-130oC
CH2CN
O n
CH2CN
b) Aromatic halide displacement
Aromatic halides, particularly those not activated by electron withdrawing groups, are best displaced by using cuprous cyanide
(1593)(1774)(1946). Thus, p-halophenol reacts with cuprous cyanide in DMSO to give p -hydroxybenzonitrile (1946):
37
OH
OH
DMSO
+ CuCN
reflux 2-5 hrs.
X
CN
X = Cl, Br, I
Cuprous cyanide and 9-bromoanthracene in DMSO give 9-cyanoanthracene in 91% yield (3247).
A procedure for the separation of isomers of dihalonitrobenzene consists of treating them with an alkali metal cyanide or cuprous cyanide
in DMSO. When a mixture of 2,3- and 3,4-dichloronitrobenzene is thus treated, only the 2,3-isomer reacts, whereas the 3,4-isomer is
recovered unchanged (1455):
NO 2
NO 2
Cl
+ N aCN
CN
DMSO
Cl
Cl
Sodium cyanide and o-fluoronitrobenzene in DMSO form 2-hydroxy-isophthalonitrile (8065):
F
OH
NO2
NC
+ NaCN DMSO
120oC, 2hrs.
CN
60%
c) Hydrogen displacement
When o-nitrobenzonitrile is heated with sodium cyanide in DMSO hydroxy-isophthalonitrile is produced (8065).
NO2
CN
OH
+ NaCN
CN
DMSO CN
o
120 C
1 hour
55%
d) Quarternary ammonium salt displacement
When 2-pyrrolylmethylammonium salts are reacted with sodium cyanide both pyrrole-2-acetonitrile and “abnormal” nitrile are produced
(8759):
CH 2 N + (CH 3 ) 3 X CN
CN
+ Na C N DMSO
8 0-85 o C N
CH 3
N
CH 3
+
NC
N
CH 3
e) Sulfinate displacement
1-Chloro-4-(methylsulfonyl)benzene (I0 and cuprous cyanide fail to react to give the desired 1-cyano-4-(methylsulfonyl)benzene when
refluxed for 24 hours in DMF. However, when equimolar amounts of I and potassium cyanide are allowed to react in DMSO for 30
minutes, a 1:1 mixture of 1,4-bis(methylsulfonyl)benzene (II) and terephthalonitrile (III) is obtained in about 80% yield (1711):
DMSO
H3 CO2S
SO 2CH3+KCN
reflux
Cl
I.
+
SO2 CH3 NC
II.
CN
III.
When 4- (methylsulfonyl)cinnoline and potassium cyanide are reacted in DMSO, 4-cinnolinecarbonitrile is produced quantitatively (1721):
CN
SO2CH 3
N
+
N
KCN
DMSO
o
20 C
N
N
100%
f) Sulfonate displacement
Sulfonates (e.g. tosylates) or disulfonates are converted in high yields to the corresponding nitriles or dinitriles with cyanides
in DMSO (477)(2525)(10044). Thus, azulene-1,3-bis(hexanenitrile) and azulene-1, 3-bis -(pentanenitrile) are prepared
by treating the corresponding tosylates (or chlorides) with sodium cyanide (2783).
A neopentyl substitution product can be obtained by treating the corresponding tosylate with potassium cyanide in DMSO
(8255):
38
O
O
DMSO
CH2 CN
+ KCN
CH2 OTs
70o C
61%
3 hrs.
g) Other displacement reactions
Reacting a chloromethyl-1,2,3,4-tetrahydropyrimidine-2-one or4-(1-chlorethyl)- 4-dihydropyridine with sodium cyanide gives the ringexpansion products (4739)(9986). Thus, the above-mentioned pyrimidine produces a 7 membered ring compound (4739):
O
O
DMSO
CH2OTs
+ KCN
CH2CN
70o C
3 hrs.
61%
Displacement of primary or secondary hydroxyl groups by nitrile groups is accomplished by a short refluxing of the alcohol and
triphenylphosphine in carbon tetrachloride, followed by the addition of DMSO and sodium cyanide to obtain 70-85% yields of the
corresponding nitriles (872).
11. Halogen Ion
Displacement of halogen or other groups by halide ions is frequently easy in DMSO. Exchange reactions between halogens often
require high temperatures and because of its boiling point of 189° C, DMSO is the solvent of choice.
a) Aliphatic halide displacement
The kinetics of homogeneous isotope exchange between 36Cl in cyclic compounds (e.g. cyclopentyl chloride, cyclohexyl chloride,
cycloheptyl chloride, cyclooctyl chloride) and lithium chloride has been studied in DMSO. This exchange is a bimolecular SN2 reaction
(109)(651):
RCl36
Cl-
+
RCl
+
Cl36 -
Similar exchange reactions between n-hexyl chlorides (containing36CI) and n-hexyl bromides (containing "Br) and lithium chloride and
bromide have also been studied in DMSO (650).
By exchanging two bromine atoms in the 1,4-positions with lithium chloride in DMSO, 1,4-di-p-tolyl-1,4-dichloro2,3-dibromo-2-butene
can be obtained (2760):
OTs Br
Br
OTs
Br
Ts=to syl
+ LiCl
OTs
DMSO
Br
Cl
Br
OTs
Br
Cl
Nucleophilic reactions between halogeno(phenyl)acetylenes and halide ions have also been examined in DMSO (10394), eg.
CPh
+ CBr + (C2H5)4N Cl
dry DMSO
PhC CCl
95 C, 125 hrs. 15%
o
b) Aromatic halide displacement
The chloride ion in chloro nitrobenzenes can be replaced by fluoride with potassium fluoride in DMSO (438):
Cl
F
+ KF
NO 2
DMSO
190 oC
14 hrs
72%
NO 2
39
Quantitative studies are reported for substitution of the type ArHal + CuX à ArX + CuHal in DMSO and other polar solvents
(541)(1593)(1214). Ease of replacement follows the order: H a I= I, Br, CI, F; X =CI,Br,I. The reaction rates are the highest in DMSO
among the solvents examined. Thus [1-36Cl]chloronaphthalene can be prepared from 1 - bromonaphthalene and radioactive cuprous
chloride (1593):
Br
Cl 36
+
C uCl 36
DMSO
reflux 1 hr.
nearly quantitative
c) Sulfonate displacement
Sulfonates (e.g. tosylates, nosylates = p-O2N-Ph-S03) can be displaced by halogens by reacting them with lithium chloride, lithium
iodide (4066)(5836), lithium bromide (4066) or sodium bromide (1027) in DMSO. Pure secondary alcohols can be converted to bromides
without rearrangement by first preparing the tosylates and then reacting them with sodium bromide in DMSO at room temperature
(1027).
Treatment of endo-5,6-bis(p-toluenesulfonyloxy-methyl)-2-norbornene with cesium chloride in DMSO gives the endo-5,6bis(chloromethyl)-2-norbornene (10002):
+ 2CsCl DMSO
CH2 OTs
100o C, 12 hrs
CH2OTs
CH2Cl
CH2Cl
50%
d) Displacement of diazonium ion
p-Nitrobenzenediazonium tetrafluoroborate in DMSO reacts with iodides, bromides and chlorides to give the corresponding phalonitrobenzene (99), e.g.:
N 2 + BF
4
-
Br
DMSO
ro o m te m p
NO
NO
70 %
2
2
12. Hydroxide Ion
The basicity of hydroxides in DMSO closely parallels that obtainable with alkoxides, as shown in Figure 10 in which acidity functions up to
26 are obtained with 0.01 tetramethylammonium hydroxide in DMSO (1172). The solubility of the hydroxides is generally low, ranging
from 7 x 103 mol/liter for sodium hydroxide (725) to 0.12 for tetramethylammonium hydroxide at room temperature (1172) (see Table IX).
Additions of water increase the solubility of alkali metal hydroxides, but the increased solubility is accompanied by a decrease in the
activity of the dissolved hydroxide ion. Figure 9 is a phase diagram of the water-DMSO-metal hydroxide systems for NaOH and KOH.
Potassium hydroxide is consistently more soluble than sodium hydroxide at a given water content. In spite of the low solubility of alkali
metal hydroxides in DMSO, satisfactory use of the strong basicity of the hydroxide ion is sometimes achieved by using a slurry of the
powdered base in the reaction.
a) Aliphatic halide displacement
When the alkaline hydrolysis of methyl iodide is studied in the presence of hydroxyl ion in DMSO-water, the rate of hydrolysis increases
with increasing DMSO content (329):
CH3 I + NaOH
DMSO-H 2 O
CH3OH + NaI
Similar results are obtained with other primary alkyl halides (iodides, bromides, chlorides)(913).
The rate constants for the reaction of hydroxide ion with ring substituted benzyl chlorides in acetone-water and DMSO-water mixtures are
reported as a function of both solvent composition and temperature. The reaction rate increases with increasing DMSO concentration but
decreases with increasing acetone concentration (432).
b) Aromatic halide displacement
The reaction of 2,4-dinitrofluorbenzene and 4-nitrofluorobenzene with hydroxide ion in DMSO-water are strongly accelerated by DMSO
(328).
40
Hydrolysis of o- and p-nitrochlorobenzenes with caustic soda in DMSO produces o- and p-nitrophenols (3925):
Cl
OH
NO 2
+ N aO H (aq)
NO 2
D M SO, air
80-115 oC
3 hours
Nucleophilic substitution reactions have also been carried out on a variety of mono- and dihalogen-1,2,3Denzothiadiazoles, e.g. 6chloro-4-fluoro-1,2,3-benzothiadiazole, with potassium hydroxide in aqueous DMSO to give the corresponding phenol (4425):
F
OH
N
N
Cl
S
DMSO (aq), KOH
reflux 2 hrs.
Cl
N
N
92%
S
41
c) Nitro group displacement
The nitro group in 4-nitropyridine N-oxide, p-nitrobenzophenone and 1-nitroxanthone can be replaced with aqueous sodium hydroxide to
give the corresponding phenols or 1-hydroxyxanthone, resp. (409)(470).
When p-dinitrobenzene is reacted with hydroxide ion in aqueous DMSO, one nitro group is displaced (6937).
13. Mercaptide (or Thiophenoxide) Ion
The mercaptide or thiophenoxide ions are known as good nucleophiles, and significant rate increases have been observed in DMSO when
compared to the same reaction in alcohols (399).
a) Aliphatic halide displacement
A number of alkyl halide displacements with mercaptides or thiophenoxides have been studied in DMSO (680) (712)(8779). Thus, the
reaction of a, a' - dibromo- a, a, a', a'-tetrafluoro-p-xylene with sodium ethyl mercaptide gives the corresponding a , a'-bis(ethylthio)xylene
(3386):
CF2Br
CF2SC 2H5
+ 2 C2H5SNa NaOCHo3, DMSO
50-60 C
2hrs.
CF2Br
CF2SC 2H5
Methyl perfluoroalkyl sulfides may be prepared by reaction of the perfluoroalkyl iodides with sodium methyl mercaptide and dimethyl
disulfide in DMSO (4792), e.g.:
n-C 6F13I
CH 3SSCH 3, DMSO
+ CH3SNa
n-C8H 13SCH3
105oC
88%
20-40 hrs.
A derivative of poly-3,3-bis(chloromethyl)oxacyclobutane is prepared by reacting it with sodium benzyl mercaptide in DMSO (6847):
Cl
H2
C O
H2
C
n
H2
DMSO
o
C
110-120 C
5 hrs. PhH 2CS
NaSH 2C
Cl
SCH 2Ph
H2
C O
n
b) Aromatic halide displacement
Aromatic halogens are replaced by mercaptide or thiophenoxide ions in DMSO (541), particularly when the aromatic ring contains
electron withdrawing groups in the ortho- or para-positions to the halogen (8344)(399). Thus, potassium benzyl mercaptide reacts with
p-fluoronitrobenzene in DMSO-methanol under mild conditions (399):
SK
O2 N
H2
C
S
DMSO
26-40oC
few min.
NO2
The reaction rate of the above reaction increases significantly with increasing DMSO concentration.
The reactions of 4-methyithiophenoxide with 3- or4-halo-substituted phthalimide derivatives have been studied in DMSO (9771):
O
CH3
X
O
O
DMSO
NR +
H3C
NaS
NR
O
Nucleophilic substitution reactions have been carried out with mercaptide or thiophenoxide ions on a variety of mono- and dihalogen1,2,3-benzothiadiazoles (4425).
c) Nitro group displacement
The nitro group at certain tertiary carbon atoms can be displaced by thiophenoxide in DMSO-methanol (1237) or
42
methyl mercaptide ions in DMSO (10008). The yields of the tertiary sulfides are very high in both cases, e.g. (10008):
(H3 C)2C
NO 2
(H3 C)2C
SCH 3
+ NaSCH 3 DMSO
15 min.
Ph
SO2
Ph
SO2
The nitro group in substituted nitrobenzenes is displaced by the thiophenoxide ion (9771) or mercaptide ion (4068) (9771) to give the
diaryl or alkyl aryl sulfides, respectively, e.g. (4068):
NO2
+ NaSR'
R
DMSO
SR'
R
d) Sulfonate group displacement
The reactions of the tosylate of 2,2,2-trifluoroethanol with the sodium salts of methyl, ethyl or 2-hydroxyethyl mercaptides in DMSO
give the expected thio ethers (589):
DMSO
CF3CH2OTs + RSNa
CF3CH2SR
14. Nitrite Ion
Sodium nitrite has good solubility in DMSO. Thus, in a few minutes, 100 cc of DMSO dissolves 19.2 g of sodium nitrite, whereas only
1.88 g dissolves in 100 cc of DMF at room temperature after 24 hours. In DMSO it is not necessary to add urea to increase the
solubility of sodium nitrite, as is the case with DMF (685). Displacement reactions involving the nitrite ion have been studied rather
extensively in DMSO.
a) Aliphatic halide displacement
The displacement of aliphatic iodide, bromide or chloride to give the corresponding nitro compound is readily accomplished in DMSO
with yields ranging from 50-91 %, depending on the structures involved (684)(3686) (4562). Primary and secondary alkyl bromides and
iodides react with sodium nitrite to produce the corresponding nitro compounds (486), e.g. 1 -bromooctane gives 1 -nitrooctane (685):
CH3(CH2)7Br + NaNO2
CH3(CH2)7NO2
66%
Lower nitroparaffins are prepared by treating the corresponding C1-3 alkyl chlorides with alkali metal nitrites in DMSO (10286):
CH3Cl + NaNO2 DMSO
CH3NO2
85%
When a -haloesters are reacted with sodium nitrite in DMSO, the nitro ester initially formed is quickly converted to the a-nitrite ester
(684):
R
Br
DMSO
CO2C 2H5 +NaNO2
R
R
CO 2C2 H5
O2N
α-nitroester
room temperature
ONO
CO2 C2H 5
α-nitrite ester
However, by adding phloroglucinol to the reaction mixture, the formation of nitrite ester is prevented and pure - nitroesters are produced
in excellent yields (682)(684)(691).
When 1,3-dihalogen compounds, such as 3-bromo-l-chloropropane, are reacted with sodium nitrite, a heterocyclic compound is
obtained, e.g. 3-nitro-2-isoxazole (366)(988):
Br(CH2 )3Cl + 2NaNO2 DMSO
0-30 oC
18 hrs
O2N
O
N
53%
Other substitutions at tertiary carbon atoms involving the nitrite ion have been studied (2565)(2566)(3490). The reaction of 1 -iodo4-heptyne with sodium nitrite in DMSO produces 1 -nitro-4-heptyne (4384)(6692):
43
DMSO
H3CH2CC C(CH2)3NO2
room temp.
45%
1hr
CH3CH2C C(CH2)3I + NaNO2
b) Aromatic halide displacement
Aromatic halides can also be displaced by the nitrite ion (8063). When 2,4-dinitrochlorobenzene is reacted with sodium nitrite in DMSO,
2,4-dinitrophenol is formed (402)(4562):
Cl
OH
NO2
+ NaNO2
NO2
DMSO
room temp.
several minutes.
NO2
NO2 80%
c) Sulfonate displacement
The reaction of the tosylate of the secondary alcohol (in the steroid or prostaglandin series) with potassium nitrite in DMSO affords the
inverted alcohol as the main product together with the corresponding nitroalkane, ketone, and alkene (10454):
R
R'
OTs
+ KNO 2
H
R
DMSO
R'
R H
H +
+
R' NO 2
OH
O
+ alkene
R
R'
15. Phenoxide Ion
DMSO enhances the rate at which halides are displaced by phenoxides (phenol, catechol, hydroquinone) almost as much as it does for
alkoxides or mercaptides (399). With ions such as naphthoxide, where a choice exists between carbon and oxygen alkylation, the reaction
in DMSO gives almost exclusively oxygen alkylation (690). DMSO is a good solvent for phenoxide ions. Thus, the polymerizations of the
dipotassium salt of bisphenol A with dihaloaromatic compounds proceeds best in DMSO when compared to other dipolar aprotic solvents
(6026). The alkylation of phenoxide is enhanced more than the alkylation of amino groups in DMSO. The phenoxide group in tyrosine can
be selectively etherified without blocking the amino group (442). DMSO is also a good solvent in the nucleophilic displacement of activated
aromatic nitro groups by phenoxides for the synthesis of aromatic ethers (10434).
a) Aliphatic halide displacement
DMSO can be used as the solvent in alkylation of sterically hindered phenols (884)(3631)(3830)(4573). When 2,6-di-tert-butyl-4methylphenoxide is reacted with ethyl iodide, the major product is the corresponding ether (517):
C2 H5 O
OH
O
O
NaH, DMSO
C2H5
room temp., 10 min.
CH3
77%
CH3
C2 H5 CH3
23%
CH3
0%
With tert-butyl alcohol as the solvent, the corresponding product distribution is 19%, 73%, 8%, and the reaction takes several days instead
of 10 minutes, as in DMSO.
When 2-t- butyl-5-methyl phenol is alkylated with allyl bromide in DMSO with sodium methoxide as a base, a 97% yield of allyl-t-butyl-5methylphenyl ether is obtained (885).
Reaction of polychloroethanes with sodium phenoxide in DMSO gives phenoxychloroethylenes (8410):
Cl
ONa
O
+
Cl2 CHCHCl2
Cl
DMSO, 70oC
5 hrs.
44
Sodium methyl salicylate and diiodomethane in DMSO give formaldehyde disalicyl acetal (6460):
2
o
CH2I2 DMSO, 145 C
24 hrs.
+
ONa
CO2CH3
O
CO2CH3
O
CO2CH3
Alkylation reactions of the bifunctional ? -bromo-1,2-epoxyalkanes have been found to be markedly dependent upon the solvent. In
alcoholic media, phenoxides react by opening the epoxide ring to give ß-hydroxy- ? - bromoalkyl derivatives. In DMSO, these same
compounds react by displacement of bromide ion to give epoxylalkyl derivatives (3395). Polyhydroxyethers can be synthesized from
mono-alkali metal salts of bisphenols, such as 4,4'sulfonyldiphenol, and 1-halo-2,3-epoxyalkanes in a one-step reaction in DMSO
(10437):
n O
-
n ( O-Ar-OH)+
Cl
R
R
Ar O
DMSO
130-140 oC
2.5 hrs.
OH O
n
A number of catechol ethers have been prepared by using DMSO as the solvent (9145). Catechol reacts with methylene chloride in
DMSO with sodium hydroxide as the base to give 1,2-methylenedioxybenzene (2887):
OH
NaOH, DMSO
+ CH2Cl2
OH
O
O
91%
b) Aromatic halide displacement
The phenoxide ions in DMSO have been used in many aromatic halide displacement reactions (399)(690). Activated fluorobenzenes
react with alkali metal salts of divalent phenols to give aryloxy compositions (8683):
HO
S
CN NaOH, DMSO
+
o
100 C, 18hrs
CN
OH
O
F
S
OH
Phenoxides also react with halo-substituted phthalimide derivatives in DMSO to produce high yields of ether imides (9096):
O
O
N R
X
+
NaO
N R
DMSO
O
O
O
The dipotassium salt of 3-hydroxybenzoic acid reacts with 3,4-dichlorobenzotrifluoride in DMSO to yield 3-(2-chloro-4trifluoromethylphenoxy)-benzoic acid (10320):
Cl
Cl
OK
KO 2C
+
K 2CO 3, DMSO
Cl
O
CF 3 138-144 o C, 22 hrs
CF 3
CO 2H
The ability of phenoxide ions in DMSO to displace aromatic halogens and the solubility of the phenoxide ions in DMSO are used in
polycondensation reactions to obtain linear, high molecular weight aromatic polyethers (6026)(6830)(7699). Thus, bisphenol A can be
polymerized with 4,4'-dichlorodiphenyl sulfone in DMSO to prepare a polyether sulfone (6831):
45
HO
Cl
S
O
SO 2
+
O
S
KOH , DMSO
n
O
O
Cl
OH
The dipotassium or disodium salt of catechol in DMSO reacts smoothly with some polyhalogenated benzenes (or heterocycles) to
give good yields of the corresponding dibenzo-p-dioxins (7553)(8311 ), e.g. (7047):
OH
Cl
Cl
OH
Cl
Cl
O
KOH, DMSO
+
reflux
Cl
81%
Cl
O
c) Nitro group displacement
Some activated nitro groups are displaced with ease by phenoxide ions (8984)(8350)(8685):
O
ONa O N
2
+
H 3C
N
HC
DMSO 3
room temp.
O
O
CH3
N
O
O
CH3
Nucleophilic displacement of activated aromatic nitro groups with aryloxy anions in DMSO is a versatile and useful reaction for the
synthes is of aromatic ethers (10434). This reaction has also found applications in polymers, particularly in the preparation of polyimides
(7710)(8287).
d) Phenoxide displacement
Polyetherimides can be made by effecting an interchange reaction, in the presence of an alkali phenoxide, between aryloxy-substituted
bisphthalimide and disodium salt of, e.g., bisphenol A in DMSO (8714):
O
PhO
N R'
N
O
O
O
O
O
+ HOArOH
NaOPh, DMSO
160oC, 1 hr
Ar
O
N
R'
N
O Ar
n
OO
OPh
e) Sulfonate displacement
The monotosylate of 2-t-butyl-1,3-propane can be transformed to phenoxyalcohol with sodium phenoxide in DMSO 6315):
HOH2 C
CH2OTs +
ONa
DMSO
50-60oC, 3 hrs
HOH2 C
O
83%
16. Sulfide (or Hydrosulfide) and Thiosulfate Ions
The sulfide and hydrosulfide ions act as nucleophiles and both these ions can be alkylated and/or arylated in DMSO. Water seems to be
a necessary component for thiosulfate solubility. The rate constant for the reaction of thiosulfate in aqueous DMSO is at least an order
of magnitude larger than in other solvents (656).
a) Aliphatic halide displacement
Polymercaptans can be produced by reacting polyhalo compounds with sodium sulfhydrate (sodium hydrogen sulfide) in DMSO, e.g.,
1,2,3-trichlorpropane and sodium sulfhydrate give the corresponding trimercaptan (6192):
46
CH2ClCHClCH2Cl + 3 NaHS
DMSO
HSH 2C
50oC , 50 min.
SH
SH
A mixture of either an aryl isothiocyanate or an aryl is ocyanide dichloride, methylene bromide, and a sulfide source, such as ammonium
sulfide or sodium sulfide, can be reacted in DMSO to provide a one-step synthesis of aromatic 2-imino-1,3-dithietanes (7528):
DM SO
N=CCl2 + CH2Br2 +2 (NH4)2 S
S
N
o
40 C
C
77%
1 hour
CH2
S
The ß-activated diethyl sulfides can be prepared by reacting the appropriate chloride with sodium sulfide in DMSO (6398):
2H3CO2CCH2 CH2Cl + Na2S.9H2O
DMSO
H3CO2CCH2 Ch2CO2CH3
62%
o
10 C
2 hrs.
Sodium thiosulfate and benzyl chloride react to yield sodium benzylthiosulfate which forms dibenzyl disulfide
(472):
DMSO (aq.)
2
CH 2Cl + 2Na 2S2 O3
CH 2S 2
CH 2S2 O3Na
30o C
2 days
b) Aromatic halide displacement
Sodium sulfhydrate can also displace aromatic halogens from activated nuclei, as in the reaction with chloro-4-nitro-3trifluorotoluene in DMSO. The major product is a disulfide (4123):
DMSO
NO2 2
Cl + NaSH
20-25oC
8 hours
NO 2
S
F3C
F3C
S
NO 2
CF3
45%
c) Sulfonate displacement
Sulfonates (tosylates) can be displaced by using either sodium sulfydrate or sodium sulfide in DMSO. Thus, 1,1-dihydrotrifluoroethyl ptoluene sulfonate reacts with sodium sulfide to give bis(1,1-dihydrotrifluoroethyl) sulfide (489):
CF3 CH2OTs + Na2 S.9H2 O
S, H2O, DMSO
CF3CH 2SCH2 CF3 + CF3CH2 S-S-CH2 CF3
70-80o C
43%
29%
2 hours
17. Thiocyanate Ion
Sodium and potassium thiocyanates are very soluble in DMSO, and in most cases, the rate constants in displacement reactions are
considerably greater than for reactions in protic solvents, e.g. methanol (471).
a) Aliphatic halide displacement
The reaction of 2-bromooctane with potassium thiocyanate yields 2-octyl thiocyanate (472):
H3C
CH(CH 2)5CH 3 + KSCN
Br
DMSO
74oC
2 hrs.
H3C
50%
CH(CH 2)5CH 3
SCN
3-Bromocyclohexene reacts with potassium thiocyanate in DMSO to form 3-thiocyanocyclohexene which is labile and rearranges to 3isothiocyanocyclohexene (390):
DMSO, 5% H2 O
+ KSCN
o
0C
Br
distill
SCN
NCS
Ammonium thiocyanate and 2-chloromethylbenzimidazole in DMSO react to form thiocyanic acid (2benzimidozolyl)methyl ester (7173):
47
N
N
DMSO
CCH2 Cl + NH 4SCN
N
CCH 2SCN
room temp
15 minutes
H
N
41% H
b) Aromatic halide displacement
Nitrotrifluoromethylchlorobenzenes react with sodium thiocyanate in DMSO to yield the corresponding phenylthiocyanates
(4123)(7158):
Cl
NO2
+ NaSCN
o
45-50 C (22 hrs.)
120oC (3 hrs.)
CF 3
NO2
DMSO
70%
CF 3
c) Sulfonate displacement
Potassium thiocyanate in DMSO displaces the sulfonate groups from 2,4-pentane di-p-bromobenzenesulfonate to
give 2,4-dithiocyanopentane (515):
OBs
OBs
+ KCN
DMSO
o
70-75 C, 50 hr
SCN
SCN
68%
Similarly, 2-methylbutyl p-toluenesulfonate and potassium thiocyanate in DMSO yield (62.5%) 2-methylbutyl thiocyanate (5435).
B. BASES AND BASE-CATALYZED REACTIONS IN DMSO
Basicities in DMSO
The reactivity of nucleophiles in DMSO mixtures with water or alcohols consistently increases as the content of DMSO in the mixture
increases. When the nucleophile is the hydroxide ion in the aqueous system, or the alkoxide ion in the alcoholic system, the activities of
the bas es can be presented in terms of acidity function, shown in Figure 10. Since the acidity function is a logarithmic scale measuring
the ability of the system to remove a proton from the reference indicator, the data show the basicity to be enhanced some 1014 fold
upon going from water or alcohol to 99% DMSO. Such a protic-aprotic system offers a means of adjusting the basicity of a reaction
medium over a wide range.
In the highly basic systems, obtained when the concentration of water or alcohol is low, an equilibrium amount of the DMSO anion will
be present. The simple aliphatic alcohols are about 1,000 times as acidic as DMSO and they have about the same acidity as
triphenylmethane (734)(1558). One chemical consequence of this effect shows up in the alkoxide-catalyzed autoxidation of fluorene
where the oxidation rate is controlled by the rate of carbanion formation (1728). The reaction rate increases 220-fold upon changing the
solvent from t-butanol to an 80:20 DMSO-t-butyl alcohol mixture. However, in the 80:20 mixture the concentration of DMSO anion is
sufficient to react with the product so that instead of a 91 % yield of fluorenone a 78% yield of the DMSO adduct of fluorenone is
obtained.
Although the equilibrium amount of DMSO anion produced by alkoxide ion in this system is small, the rate at which the protons transfer
is fast (1758)(1759) so that a steady pool of DMSO anion is available for reaction.
Proton Removal
A number of different reactions require the removal of protons from carbon with the resultant formation of carbanions. The proton removal
can be either an initial or the rate-determining step. Carbanions are formed in racemizations, in isomerizations and in a wide variety of
elimination reactions. Just as the equilibrium basicity of alkoxides and hydroxides is enormously enhanced in DMSO versus in hydroxylic
solvents, so also is the rate at which proton removal or hydrogen exchange reactions occur in DMSO. The rate of potassium t-butoxidecatalyzed hydrogen-deuterium exchange at a benzyllic carbon atom is 10 6 times greater in DMSO than in t-butanol (606).
A similar rate enhancement is observed in racemizations using ammonia as the base, with the reaction being 106-107 times faster in
DMSO than in t-butanol (622)(524). The influence of the cation is greater in DMSO than in t-butanol. For example, in t-butanol, sodium
and potassium t-butoxides are about equally effective in prompting hydrogen exchange, whereas in DMSO the potassium salt gives a
reaction rate one hundred times that of the sodium salt (606).
48
49
The table below (Table XI) lists the acidities (pKa) values of 132 organic compounds in DMSO, starting with the most acidicprotonated pyridine, and ending with the least acidic-propionitrile (10569). The pKa of DMSO is 35 (10411).
TABLE XI
Acidities in DMSO
COMPOUND
Protonated pyridine
2,6-Dinitro-4-chlorophenol
Protonated analine
Protonated 2-methylpyridine
Protonated 2,4-dimethylpyridine
Protonated o-phenylenediamine
Thiosalicylic acid
Phthalic acid I
Oxalic acid I
Sulfamic acid
Salicylic acid
Thioacetic acid
Thiocyanuric acid
Bromocresol green
2,5-Dihydroxybenzoic acid
Phenylsulfonylnitromethane
3,5-Dinitrobenzoic acid
2,4-Dihydroxybenzoic acid
Rhodanine
Nitromethyl phenyl ketone
9-Cyanofluorene
2,5-Dihydrophthalic acid
Protonated tributylamine
Protonated diphenylguanidine
Chloroacetic acid
p-Nitrobenzoic acid
Ethyl nitroacetate
Thiophenol
Protonated dibutylamine
Bromo thymol blue
p-Chlorobenzoic acid
9-Carboxymethylfluorene
9-Phenylsulfonylfluorene
Protonated piperidine
Protonated pyrrolidone
Benzoic acid
o-Toluic acid
m-Toluic acid
Malononitrile
p-Toluic acid
3-Nitro-l-propene
Phenylacetic acid
Thiophenylnitromethane
Phenylnitromethane
Methylmalononitrile
Acetic acid
2-Thiohydantoin I
Acetylacetone
Hydrogen cyanide
Bis(ethylsulfonyl)methane
2,4-Dinitroanaline
Oxalic acid II
Resorcinol
9-Phenylthiofluorene
2,5-Dihydrophthalic acid II
Nitrocycloheptane
Nitrocyclopentane
p-Chlorophenol
2,5-Dichloro-4-nitroanaline
Nitromethylcyclopropane
Nitroethane
1,1 Bis(ethylsulfonyl)ethane
1 -Nitropropane
2-Nitropropane
Phenol
m-Cresol
pKa
3.5
3.6
3.7
4.0
4.5
4.8
5.2
6.2
6.2
6.5
6.8,6.6
6.7
6.7
7.0
7.1
7.2
7.3
7.5
7.7
7.7
8.3
8.3
8.3
8.6
8.9
9.0
9.2
9.8
10.0
10.2
10.2
10.2'
10.3
10.6
10.8
10.8,10.9
11.0
11.0
11.1
11.2
11.2
11.6
11.8,11.9
12.2
12.4
12.6
12.8
13.6
13.7
14.4
14.8
14.9
15.3
15.4
15.6
15.8
16.0
16.1
16.2
16.5
16.7
16.7
16.8
16.9
16.9
17.0
COMPOUND
Nitromethane
Diphenylacetonitrile
a, a, a', a'-Tetraphenylacetone
Phenyl benzyl ketone
Bis(2-nitrophenyl)amine
Nitrocyclobutane
9-Phenylfluorene
Nitrocyclohexane
Nitroneopentane
a, a-Diphenylacetophenone
a-Thiophenylaceton
Methyl trifluoromethyl sulfone
4-Chloro-2-nitroanaline
4-Nitroanaline
a, a-Diphenylacetone
Methyl benzyl ketone
2-Bromofluorene
Ethyl trifluoromethyl sulfone
Thiourea
Thiophenylacetonitrile
Bis(n-chlorophenyl)amine
Phenylacetonitrile
9-Methylfluorene
Phenylacetylene
2,6-Dichloroanaline
Fluorene
Trithiophenylmethane
Phenyldithiophenylmethane
1 -Phenyl-1 -cyanoethane
3-Methylfluorene
2,4 Dichloroanaline
3-Methoxy-1 -propyne
Formamide (N-H)
Diphenylamine
Dibenzyl sulfone
N,N-Dimethylprop-2-ynylamine
9-tert-Butyl-fluorene
Ethyl phenyl ketone
Diphenylmethylphenyl sulfone
2,5-Dichloroanaline
Acetophenone
Urea
2,4-Dichloroanaline
Acetamide (N-H)
Methyl benzyl sulfone
1,3,3-Triphenylpropene
Isopropyl phenyl ketone
Acetone
9-(3-Chlorophenyl)xanthene
3-Chloroanaline
Diphenylthiophenylmethane
Nitrocyclopropane
Diethyl ketone
9-Phenylxanthene
Water
Benzyl methyl sulfoxide
Methyl phenyl sulfone
Diphenylyldiphenylmethane
Triphenylmethane
Phenylthiophenylmethane
Ethyl phenyl sulfone
Dimethyl sulfone
Acetonitrile
Diphenylmethane
Propionitrile
DMSO
pKa
17.2,16.5
17.5
17.6
17.7
17.7
17.8
17.9
17.9
18.1
18.7
18.7
18.8
18.9
19.2
19.4
19.8
20.0
20.4
20.5
20.8
21.4
21.9
22.3
22.6,28.8
22.6
22.6
22.8
23.0
23.0
23.1
23.4
23.5
23.5
23.5,23.6
23.9
24.2
24.3
24.4
24.5
24.6
24.7
25.1
25.3
25.5
25.6
25.6
26.3
26.5
26.6
26.7
26.7
26.9
27.1
27.9
28.0
29.0
29.0
29.4
30.0,30.6
30.8
31.0
31.1
31.3
32.3
32.5
35
50
ELIMINATION REACTIONS
These are base-catalyzed reactions in which two atoms or groups are removed or eliminated, usually from one or two carbon atoms. A
double bond is frequently formed as the result of this elimination.
1. Cope Elimination
The pyrolysis oft-amine oxides (Cope elimination) in dry DMSO proceeds at a convenient rate at 25°C to give 80-90% yields of olefins.
Temperatures of 132-138° are usually required in water. In addition, the rates in DMSO are 10,000 times faster than in water (495):
O
(CH3)3
DMSO
N
25 oC
Ph
Ph
+
Ph
CH3
80-90%
The rate is higher in wet DMSO than in dry THF because DM SO acts as an internal drying agent and competes with amine oxide for the
water present (578).
5 a-Stigmasta-7,22,25-trien-3 ß-ol, a steroid alcohol, is obtained by heating the appropriate t-amine oxide in DMSO (3481):
O
N
R
(CH3)2
DMSO
120-130oC
R
H3C
61%
H3C
2. Decarboxylation and Decarbalkoxylation
DMSO promotes the decomposition of malonic (640), oxalic (604), and oxamic (643) acids at elevated temperatures, e.g. 140-160 °C.
Pyridylacetic acid hydrochloride decarboxylates in DMSO at moderate temperatures. The only product of this decarboxylation is 4 methyl-pyridine hydrochloride (2343)(3743):
DMSO
ClHN
CH2CO 2H
ClHN
30 oC
CH3
95+%
The decarboxylation of trichloroacetic acid also occurs as low as 25.0 °C in the presence of DMSO and water. The reaction rate constant
increases by a factor of 6-7 with a change in concentration of DMSO from 50 to 86%. Dramatic rate accelerations result in the
decarboxylation of benzisoxazole-3-carboxylic acids if water is replaced by DMSO (3447):
CO2H
X
N
Y
DMSO, 30 oC
O
X
CN
+
Y
CO2
OH
Some acids, such as optically pure (+)-2-benzenesulfonyl-2-methyl-octanoic acid, decarboxylate more readily in the presence of base
to give, in this case, (+)-2-octylphenylsulfone in 98% optical purity (631):
Ph
O2
S
CO 2H
H3C n-C H
6 13
O2
S
KOCH 3 , DMSO
90o C, 148 hrs.
Ph
CH3
83%
n-C6 H13
Tetrahalophthalic acids in DMSO in the presence of alkali and alkaline earth chlorides undergo double decarboxylation to form 1,2,3,4tetrahalobenzenes, whereas, in the presence of other chlorides (e.g. CoCl 2, NiCl2, CuCI2) or no salts at all mostly single decarboxylation
occurs to give 2,3,4,5-Cl4(or Br4)C6HCO2H (4602). Lead tetraacetate has been used in DMSO to decarboxylate dicarboxylic acids (5081).
Thus, the treatment of 3,3-dimethylcyclohex-4-ene-1,2-dicarboxylic acid yields 3,3-dimethyl-1,4-cyclohexadiene (7533):
51
CO2H
Pb(OAc)4, DMSO-pyridine
CO2H
Rates of decarboxylation are reported for several phenylmalonic acids and esters in DMSO at 55.4°C. Only those compounds bearing at
least one carboxylic proton are labile, which establishes that intramolecular proton transfer is an integral part of the reaction mechanism
(7655).
Benzaldehydes can be prepared from the phenylacetic acids by electrolytic decarboxylation and oxidation in DMSO in the presence
of sodium hydride. The yields are good in most cases (8766):
CHO
CH2CO2H electrolysis
R
R
NaH
Decarbalkoxylation (mostly decarbethoxylation) is related to decarboxylation in that the -CO2R group, instead of CO2
(decarboxylation) is eliminated. Thus, geminal dicarboxy groups are eliminated when malonic ester derivatives are heated in DMSO
(942):
NaCN, DMSO C2H5O2C
C2 H5O2C
160oC, 4 hrs.
C2 H5O2C
H
60-80%
The treatment of ethyl trichloroacetate with sodium methoxide in DMSO at 0 °C produces dichlorocarbene which is oxidized by
DMSO (1040).
Decarboxylation of geminal diesters, ß-keto esters, and a-cyanoesters to the corresponding monoesters, ketones and nitriles can
be accomplished in excellent yields (85-95%) in wet DMSO in the presence of sodium chloride at 140-186°C (6102)(7022)(9769).
Other dipolar aprotic solvents, such as DMF, are less effective in the case of substrates with lower activity because of lower boiling
points of these solvents (6102).
The alkylative decarboxylation of N-carbalkoxypyrozoles has been shown to require a polar aprotic solvent, such a DMSO, and to
be subject to catalysis by nucleophiles, e.g. halide ions (7285):
N
X-, DMSO
N
R
N
CO2R
N + CO2
The decarbalkoxylation of methyl or ethyl isohexylmalonates in DMSO in the presence of various alkali metal salts gives methyl or
ethyl 6-methylheptanoates. The best results are obtained in the presence of 1 equivalent of salt and 2 equivalents of water (8861).
Salts such as KCN, NaCl, or LiCl dramatically enhance the decarbalkoxylation rates of geminal diesters, ß-keto esters, and acyanoesters by DMSO-water (9769).
3. Dehalogenation
By a proper choice of reaction conditions or nucleophile in DMSO, one can obtain elimination of either bromine or hydrogen bromide
in cases where both paths are available (454):
H2CSOCH3, DMSO
H2CSOCH3, DMSO
Br
Br
71%
Br
61%
In the presence of excess dimsyl sodium in DMSO at room temperature, the debrominated intermediate results, while the use of a
larger excess of dimsyl sodium and longer reaction times yield 1,2-cyclononadiene.
In the reaction of 3 ß-chloro-5 a-bromo-6 ß-bromocholestane with excess dimsyl sodium in DMSO, bromine elimination occurs.
When this intermediate is treated with potassium t-butoxide in DMSO, HCl elimination occurs (455):
52
H2CSOCH3, DMSO
room temperature
Cl
Br
Cl
Br
77%
t-BuOK, DMSO
43%
Pure olefins from their dibromides can be obtained by using sodium thiosulfate in DMSO as the debrominating agent. Thus,
stilbene dibromide yields stilbene (6496):
Br
Br
+ Na2S 2O2
DMSO
o
60 C, 8 hrs.
99%
Treatment of 8,9-dibromodispiro[2.0.2.4]decane with potassium t-butoxide in DMSO gives spiro[2.0.2.4]dec-8
ene (7153):
Br
Br
t-BuOK, DMSO
room temperature, 20 hrs
Another dibromide can be dehalogenated by heating with zinc dust in DMSO (7184):
OAc
OAc
Br
DMSO, Zn
o
90 , 2.5 hrs
Br
OAc
OAc
100%
Heating trans - a, ß-dibromo derivatives of diphenylethylene and meso-stilbene with potassium fluoride and cesium fluoride in
DMSO afford quantitative yields of diphenylacetylene and trans -stilbene, resp., via the intermediacy of dimsyl ion. These
reactions do not occur in N-methylpyrrolidone, DMF, or sulfolane (9338):
Br
Ph
Br
Ph
Ph
Br
Br
DMSO
KF or CsF
PhC CPh
DMSO
Ph
The action of zinc-copper couples on perfluoroiodoalkanes, C 4 F 9 I, C 6 H33I and C sF17 I, has been studied in aprotic solvents,
such as DMSO. A mixture of perfluoroolefins results (9928),' e. g.
C4F9I
Zn-Cu, DMSO
80oC
F3C
F
F
+
CF3
39%
F3C
F
CF3
F
21%
+ C4F9H
20%
53
Some dehalogenation reactions using potassium t-butoxide as the base have been reviewed (6815).
4. Dehydrohalogenation
A variety of bases have been used in the dehydrohaloge nation reaction. The most frequently used base has beer potassium t-butoxide,
followed by other alkoxides. Other bases used include: sodium and potassium hydroxide the carbonate and bicarbonate ions, quaternary
ammonium hydroxide, dimsyl ion, sodium cyanide and some relatively weak organic bases, such as ammonia and amines.
The effects of base strength and size upon the orientation in base-promoted ß-elimination reactions have beer studied
(6234)(6378)(6818)(8582)(10011).
Ionic association in base-promoted ß-elimination reactions has been reviewed (8050).
a) Potassium t-butoxide in dehydrohalogenations
The enhanced basicity of potassium t-butoxide in DMSO has been suggested as the dominant factor which causes dehydrobrominations
to occur much more readily in DMSO than in t-butanol (652).
The reaction of benzhydryl chloride with potassium t-butoxide in t-butanol occurs slowly by displacement giving benzhydryl t-butyl ether,
whereas the base in DMSO causes a very rapid elimination( a-elimination) giving nearly quantitative yields of tetraphenyl ethylene (696).
The rapid reaction is suggested to occur by an initial formation of the carbanion which eleminates chloride ion to give a carbene
intermediate, as shown below:
DMSO
[Ph2CCl]-K+
Ph2C:
PhC:
Ph2C: (or [Ph2CCl-]) DMSO
+
+ ClPh
+K+
Ph
Ph
Ph
The rate of dehydrobromination of 2-arylethyl bromides with potassium t-butoxide in t-butanol-DMSO mixtures increases with
increasing DMSO concentration at a much faster rate than the increase of acidity function (833).
The strongly basic reaction medium obtainable with potassium t-butoxide in DMSO in the case of aromatic bromine compounds
produces aryne intermediates (434)(514) (see also Displacement reactions Alkoxide Ion, Aromatic halide displacement, p. 20).
2,7-Dichlorobicyclo[2.2.1 ]heptane on treatment with potassium t-butoxide in DMSO gives 7-chlorobicyclo[2.2.1] heptene (3360):
Cl
t-BuOK, DMSO
Cl
room temperature
3.5 days
Cl
96%
Olefinic products from reactions of a series of 2-bromoaIkanes with potassium t-butoxide are produced. The transcis 2-alkene ratio is
dependent upon the alkyl group of the 2-bromoalkane (3368):
H2CR
CH3 t-BuOK, DMSO
RH 2CHC CH2 + RHC CHCH 3
o
30-90
C
Br
The trans-1 -iodocyclopropylpropene reacts at least ten times faster with potassium t-butoxide in DMSO than the cis isomer to yield 1
-cyclopropyl-2-methylacetylene (3503)(4176):
I t-BuOK, DMSO
H
CH3
fast
CH3
trans
t-BuOK, DMSO H
slow
I
CH3
cis
Six or seven-membered trans -cycloolefins may be transformed into the corresponding 3-alkoxycycloalkynes by reaction with
potassium t-butoxide in DMSO (3707):
Br
OR
(CH 2)n
OR
t-BuOK, DMSO
o
20 C, few seconds
or minutes
(CH 2)n
60-74 %
n = 5 or 6
54
The reaction of 1,1 -dichloro-1 -cyclopropylethane with potassium t-butoxide in DMSO gives 1 -cyclopropylacetylene
(5594):
Cl
t-BuOK, DMSO
CH 3
room temperature
Cl
34%
Similarly, treatment of pinacolone dichloride with potassium t-butoxide in DMSO produces tert-butylacetylene in high yield (7608):
Cl
(H 3C) 3CC Cl
H3C
t-BuOK, DMSO
(H 3C) 3C CH
95+%
below 40oC
3,3-Dimethylcyclopropene is easily produced from 1 -bromo-2,2-dimethylcyclopropane (7028):
H3 C
CH3
CH3
t-BuOK, DMSO H3 C
H
Br
90oC, 3hrs
84%
1-Bromo-2-chloro-2,2-difluoro-l-phenylethane reacts with potassium t-butoxide to give a-bromo- ß, ßdifluorostvrene (5980):
Cl
F
F
Ph
Br
t-BuOK, DMSO Ph
50oC, 4 hrs.
Br
F
F
cis-3-Bromocyclodiene is easily dehydrobrominated to 1,2-cyclodecadiene (8960):
Br
t-BuOK, DMSO
(CH 2) 7 C
o
20 C, 5 min.
78%
Dehydrofluorinations can also be accomplished with potassium t-butoxide in DMSO (5118):
F
H
F t-BuOK, DMSO
H
F
H
o
120 C, 24 hrs.
b) Other alkoxides in dehydrohalogenations
Other alkoxides, such as sodium and potassium methoxides or ethoxides, have been used with good results in dehydrohalogenation
reactions.
The olefinic products observed in reactions of sodium ethoxide or 2,2,2-trifluoroethoxide with 2-butyl iodide, bromide and chloride in
DMSO are reported (3853):
CH 3
X
o
25 C, 10 min
H3CH 2CHC CH2+ H2CHC CHCH 3
2-butene
NaOC2H5 (or NaOCH2CF3), DMSO 1-butene
X = I, Br, Cl
In all cases in the above reaction, the change from ethoxide to 2,2,2-trifluoroethoxide results in a decrease in the percent 1 -butene
(3853).
Treatment of 3-chloro-3,4-dihydro-2,2-dimethoxypyrans with an excess of sodium ethoxide in DMSO produces the corresponding apyrones (5834). (7737):
55
R3
OCH 3
OCH 3
O
R2
NaOCH 3, DMSO
R3
room temp., few hours R
Cl
O
O
2
R1
R1
The addition of DMSO to the NaOCH -CH3OH medium causes a significant increase in the rate of dehydrochlorination of Ph2CHCH2Cl
(9142)(9143). Although double dehydrobromination of 2,6,6-bis -(ethylidenedioxy)-3,7-dibromobicyclo[3.3.0]octane with ethanolic
potassium hydroxide requires refluxing for several days for complete reaction, the elimination may be effected in several hours with
sodium methoxide in DMSO (9604):
O
O
O
O
NaOCH 3, DMSO
Br
Br
o
60-70 C, 2.5 hrs
O
O
O
89-92%
O
c) Dimsyl ion in dehydrohalogenations
Treatment of 1-acetylnaphth-2-yl 2'-chloroallyl ether with dimsyl ion in DMSO yields 1-acetylnaphthyl-2-yl propargyl ether which cyclizes
to 2-methyl- l,4-phenanthrenequinone (7552):
O
O
O
O
O
DMSO
CH 2SOCH 3
O
30%
55-60%
Reaction of 2,2-dimethyl-3-dimethyl-3-chloro-3-butenoic acid with dimsyl sodium in DMSO gives 2,2-dimethyl-3-butynoic acid (7865):
CH3
CO2H
CH3
Cl
CH3
CO2H 88%
CH3
CH2SOCH 3
DMSO 50oC, 5 hrs
In some cases, potassium t-butoxide is a better dehydrohalogenating agent than the dimsyl ion. Thus, the dimsyl ion can act as a
dehalogenating agent for vicinal dibromides (455):
CH 2SOCH 3,DMSO
Br
Br
Br
Br
37%
t-BuOK, DMSO
+ styrene
78%
22%
d) Hydroxylic bases in dehydrohalogenations
Hydroxylic bases, such as sodium hydroxide, potassium hydroxide and tetraalkylammonium hydroxide have been used for ß dehydrohalogenation reactions (8050). Tetra methylammonium hydroxide is more soluble in DMSO than either sodium hydroxide
or potassium hydroxide (see Table IX). Thus, 1,1,1 -chlorodifluoroethane can be dehydrochlorinated to vinylidene fluoride in high
yield in heterogeneous DMSO suspensions or aqueous DMSO suspensions or solutions in the presence of sodium hydroxide,
potassium hydroxide or tetramethylammonium hydroxide (5279), e.g.:
H3CCClF2
+
NaOH
DMSO + H2O (5%)
o
50 C
H2C CF 2
69.8 % conversion
99.5% selectivity
DMSO is a better reaction medium for the above reaction than some other solvents.
Methyl halogenated ethyl sulfides can be dehydrohalogenated with potassium hydroxide in DMSO (3142), e.g.
56
F
F Cl
SF
+
KOH
DMSO
H3CFSC CFCl
room temperature
H
6-Hydroxy-2-isopropenyl-5-acetylcoumaran can be obtained from the corresponding vinyl bromide by dehydrohalogenation with
potassium hydroxide and cyclization in DMSO (4892):
O
O
Br
KOH, DMSO
20oC
OH
OH
O
O
42%
Relatively high yields of alkynes can be obtained from a, ß-dihalides or a, a-dihalides in short reaction tim es at moderate temperatures
in DMSO using moderately strong bases, such as potassium hydroxide, without isolation of the intermediate olefin (8238), e.g.:
Cl
DMSO, KOH
(H3C) 3 CHC CHCl
130-160oC
Br
(H 3C) 3C CH
91%
e) Weak bases in dehydrohalogenations
Although potassium t-butoxide in DMSO is an extremely strong and reactive base-solvent system, sometimes undesirable reactions take
place after dehydrohalogenations. Thus, the freshly formed olefins tend to isomerize, and carbanions can be generated which can
decompose in various ways (4180)(6163).
Dehydrohalogenations without olefin isomerization can sometimes be accomplished by using weaker bases, such as carbonates,
cyanides, or amines.
Thus, the treatment of 1,3-dibromo-1,3-diphenylcyclobutane with sodium cyanide in DMSO produces 1,3diphenylcyclobut-2-enyl
cyanide (4077):
Br
DMSO-CH3CN
Ph
Ph
Br
Ph
Ph
CN
NaCN
In the above reaction, both the ß-elimination and displacement (substitution) reactions take place.
3,3-Dibromo-6-dibromomethyl-5-carbethoxy-2,3-dihydro-2-methyl-4H-pyran-4-one with sodium carbonate in DMSO yields 3-bromo-6dibromomethyl-5-carbethoxy-2-methyl-4H-pyran-4-one (6215):
O
Br
Br
O
CO2C2H5
DMSO
Br
+ Na2CO3
20oC, 3 hrs H C
CHBr 2
3
H3C
CO2C2 H5
55%
CHBr 2
3-Alkylthio- or3-arylthio-4-chlorothiolane 1,1-dioxide can be dehydrohalogenated when warmed with triethyl. amine in DMSO (385):
SR
Cl
O
SR
DMSO
+(C2 H5)3 N o
90 C, 2 hrs.
O
60-90%
5. Nitrogen Elimination
Elemental nitrogen can be eliminated from a number of compounds by heating in DMSO in the presence or absence of bases. Usually
these are compounds that contain the nitrogen-nitrogen bond, such as hydrazones, hydrazides, carbazides, azo compounds,
57
diazomethane derivatives, azides, diazonium salts and others.
Addition of hydrazones of aldehydes and ketones to a solution of potassium t-butoxide in DMSO produces an immediate evolution of
nitrogen and formation of the corresponding hydracarbons in 60-90% yields. The reaction of the benzophenone hydrazone is typical
(495).
t-BuOK, DMSO
Ph2C NNH2
25oC
PH2CH2
+ N2
The above reaction, the so-called Wolff-Kishner reduction in DMSO, can be run even at room temperature.
The rate of the Wolff-Kishner reaction of benzophenone hydrazone in mixtures of butyl carbinol and DMSO in the range of 100-190°C
increases as the concentration of DMSO is increased, but this effect passes through a maximum. The maxima tend to drift
toward higher DMSO concentrations as the temperature is lowered (377).
The thermal decomposition of norbornan-2-one and norborn-5-en-2-one tosylhydrazone sodium salts has been studied over the
temperature range 100-150°C in DMSO and two other solvents. First order kinetics have been observed in all cases (8955):
N-N-OTs DMSO
117.5oC
+
N 2 + OTs-
Treatment of 1-acylsemicarbazides in DMSO with air or oxygen gives rise to carboxamides in good yields (3721):
O
R'
N
H
H
N
H
N
O
O2, KOH, DMSO O
R"
R" 100-110 oC R'
N
H
+ N2
+ CO
Thermal decomposition of two azobisamidines and their conjugate acids has been studied in DMSO (4748).
Rate coefficients are reported for the reaction of diazodiphenylmethane with benzoic acid and its orthosubstituted derivatives in DMSO
and other solvents (2765):
Ph2CN2
+
RCO2H
DMSO
RCO2CHPh2
+
N2
o
30 C
Thermal decomposition of several diazirines has also been investigated in DMSO (4906)(5635), e.g.
Ph
Cl
N
N
DMSO
60-90oC
N2 + PhClC
Cl
diazirine
Cl
NN
Ph
Ph
Sodium azide in DMSO reacts with a-bromophenylacetonitrile to yield benzonitrile (10077):
Ph
DMSO
CN + N 3
-
PhCN + N 2 + CN
90%
Br
Diazonium salts can be prepared in DMSO by diazotizing primary amines with sodium nitrite. In the case of benzylamine, benzaldehydes
can be prepared in good yields (167), e.g.:
NH 2
+ NaNO 2 + H +
R
R
CH 3
C S
H2 CH
DMSO
R
CH 2 + OS(CH 3)2
-N 2, H 2O
R
CHO + CH3SCH3
3
Benzenediazonium tetrafluoroborate in DMSO decomposes instantaneously with evolution of nitrogen upon addition of a DMSO solution
of choline or tetramethylammonium hydroxide (5124):
N2+ +
X
OH-, DMSO
20oC
X
+N2
58
When p-nitrobenzenediazonium tetrafluoroborate is decomposed in the presence of DMSO-benzene or DMSOnitrobenzene systems, the
respective biphenyl derivatives are obtained in good yields (5642).
The dediazotization of aromatic diazonium ions has been reviewed in various solvents, including DMSO (9423).
6. Sulfenate Elimination
The t-butoxide ion or dimsyl ion in DMSO has been used to eliminate sulfenates from sulfoxides to produce olefins in moderate to high
yields (501)(203)(672). When a number of 3-phenyl-2-alkylpropyl sulfoxides is allowed to react in DMSO with a large excess of dimsyl
sodium, cyclopropanes and olefins are formed (396)(2842):
R
Ph
CH2SOCH 3 + H2CSOCH3
+
DMSO
Ph
60-70oC, 48 hrs.
CH3SO -
R
When isomeric 2-phenylsulfinyl-1,2-diphenyl-l-ethanols are pyrolyzed in DMSO in the presence of trace quantities of pyridine,
deoxybenzoin is formed (4776):
O S Ph pyridine, DMSO
PhC=CHPh
PhCHCHPh 119oC
OH
OH
PhCCH2 Ph + PhSOH
O
3-Phenylindole is obtained from ß-hydroxysulfoxide on treatment of the latter with dimsyl ion in DMSO (5300):
Ph
Ph
SOCH 3
DMSO
OH
+
NH 2
H2CSOCH 3
N H
7. Sulfonate Elimination
Various bases have been used in the reaction of sulfonate esters of primary and secondary alcohols to give alkenes. Some of these
bases are potassium t-butoxide, sodium methoxide, potassium ethoxide, phenoxides, and others. In a few cases, elimination reactions
involving sulfonate esters have been achieved without the presence of a base by the action of heat alone.
a) Potassium t-butoxide in sulfonate elimination
Most ß-eliminations involving sulfonate esters seem to have been investigated with potassium t-butoxide as the base. Sulfonate esters
of cyclic and secondary acyclic alcohols react rapidly with potassium t-butoxide in DMSO at 20-25°C to give about 80% yields of alkenes
and no appreciable quantities of ethers. Esters of normal primary alcohols and of cyclohexylcarbinol give only 20-25% alkenes and 6070% ethers, as the result of displacement reactions in the latter case (491).
Mesylate and tosylate derivatives of cholesterol, all easily prepared, undergo facile reactions in DMSO at room temperature to afford
excellent yields of dienic materials (965).
Treatment of the tosylate of (+)-(S)-3-methyl-7-deutero-octen-4-ol-7 with potassium t-butoxide in DMSO yields (+)-(S)-cis,trans -3methyl-7-deuterooctadiene-4,6 (3482):
t-BuOK, DMSO
80oC
H3C
D
OTs
D
CH3
The tosylate of cyclohexanol-2,2,6,6-d4 on treatment with potassium t-butoxide gives cyclohexene-1,3,3-d3 (3584) :
H
D
D
OTs
D t-BuOK, DMSO D
D room temperature
D
D
36%
5,6 Dimethylenebicyclo[2.2.0]hexene-2, the Dewar o-xylylene, can be obtained by reacting the corresponding ditosylate with potassium
t-butoxide in DMSO (3827):
59
OTs
CH 2
t-BuOK, DMSO
room temp.
40%
OTs
CH 2
When 4- hydroxy-trans-bicyclo[5.1.0] octane p-bromobenzene-sulfonate is treated with potassium t-butoxide in DMSO, it is rapidly
converted to trans-bicvclo[5.1.0]oct-3-ene (4039):
OBs t-BuOK, DMSO
o
H 20-25 C, 30 min.
When 2-butyl and 2-pentyl halides or tosylates are treated with tetraethylammonium fluoride in acetonitrile, an olefin forming elimination
takes place and an overwhelming Saytzeff orientation is observed. These results are compared with results of the elimination in other
base-solvent systems, including potassium t-butoxide in DMSO (4524).
The reaction of trans -2-methylcyclooctyl tosylate with potassium t-butoxide in DMSO for 30 min at 25°C yields cis -3-methylcyclooctene,
93%, and cis -1 -methylcyclooctene, 4%. With t-butenol as the solvent, the ratio of the isomers is 2:1.
An approximately equimolar mixture of bicyclo[5.2.0]non-1 (9)-ene and bicyclo[5.2.0]non-8-ene is obtained by treatment of 8methanesulfonyloxybicyclo[5.2.0]nonane with potassium 1-butoxide in DMSO (9727).
t-BuOK, DMSO
20oC, 15 hrs.
OMs
65% total
b) Sodium methoxide in sulfonate elimination
Benzenesulfonates of typical primary and secondary alcohols react rapidly at room temperature with sodium methoxide in DMSO to
give high yields of alkenes and/or alkyl methyl ethers. Except for cyclohexyl benzenesulfonate, the ether-alkene ratio is higher in
reactions with sodium methoxide than with potassium t-butoxide. This indicates that the displacement reactions are favored over
elimination reactions with sodium methoxide in most cases (580).
1,3 -Dimethoxypropene can be obtained from p-toluenesulfonate of 1,3-dimethoxy-2-propanol by means of sodium methoxide in DMSO
in good yield with cis/trans ratio of 2.1:1. Evidently little of the displacement reaction goes on (3875):
CH2OCH 3
CH 2OCH3
NaOCH3, DMSO
TsO
CH2OCH 3
71%
CHOCH 3
A double bond in a cyclic system, a precursor of dl-juvabione, is introduced by treatment of a tosylate with sodium methoxide in
refluxing methanol containing 10% DMSO (6947).
c) Other bases in sulfonate elimination
When cyclohexyl tosylate is reacted with potassium t-butylmercaptide in DMSO, cyclohexene is the major product. However potassium
t-butoxide reacts much more ranidly than the mercaptide (496).
The effect of base strength upon orientation in base prompted elimination reactions has been studied. 2-Butyl p-toluenesulfonate is
reacted with the following bases in DMSO: potassium t-butoxide, potassium ethoxide, potassium phenoxide, potassium 4methoxyphenoxide, potassium 4-nitrophenoxide and potassium 2nitrophenoxide. The results are completely consistent with a correlation
between orientation and base strength (882).
The trans:cis olefin ratios have been determined for the elimination reactions of 1-benzylethyl tosylate, PhCH2CH(OTs)CH3, in different
base-solvent systems. The basicity of the nucleophile does not appear to significantly affect the trans:cis ratio (8372).
d) Sulfonate elimination without a base
DMSO has been found to be an excellent non-reacting solvent for the decomposition of (-)-menthyl, ß-cholestanyl, cyclohexyl and 2octyl aryl-sulfonates to the corresponding olefins. The sulfonates are heated at 89-91°C for 6 hours without a base (408).
The elimination reactions of some secondary acyclic and medium sized ring cyclic alcohol tosylates carried out in DMSO at 50°C and
90-95°C show that olefins are formed, especially with secondary alcohol tosylates.
8. Water Elimination-dehydration
Many alcohols can be dehydrated in DMSO to olefins. Certain diols when heated in DMSO lead to cyclic ethers. A group of tertiary
alcohols, such as 2-alkylcycloalkanes, at 160-190°C for several hours in DMSO give endocyclic olefins, 1 -alkylcycloalkenes, as the
major products. Thus, 1 -methylcyclopentanol gives only 1 -methylcyclopentene (394):
60
CH 3
DMSO
CH 3
160oC
6 hours
OH
88%
When certain diols are heated in DMSO, cyclic ethers result instead of the expected dienes (395). When 1,4-butanediol, 1,5-pentanediol
and 1,6-hexanediol are heated, using 2 moles of alcohol per mole of DMSO, the corresponding heterocycles, tetrahydrofuran (70%),
tetrahydropyran (47%), and oxepane (24%) are formed (394):
H2
C
DMSO
HOCH 2(CH 2)nCH 2OH
O
(nH2C)
190 oC
24-70%
C
H2
14-24 hrs.
n=2, 3, 4
2,4-Di(2-hydroxy-2-propyl)cyclohexene can be selectively dehydrated to 2-(2-propenyl)-4-(2-hydroxy-2-propyl)1-cyclohexene in DMSO
(4775):
DMSO
HO
OH
190 oC
1.5 hrs.
80%
OH
Heating of 2,2,3,3-tetramethylbutane-1,4-diol in a sublimation apparatus in DMSO gives the tetrahydrofuran (4934) :
CH 3 CH 3
CH 2OH
C
C
H 3C
DMSO
CH 2OH
CH 3 CH 3
H3C
CH 3
H3C
160 oC
16 hrs.
CH 2
H2C
42%
O
In the dehydration of 1,4-diols, a cyclic transition state with DMSO has been postulated (395)(6098):
H
O
O
CH 3
S
O
H3C CH
3
H
CH 3
When sec- or tert-benzylic alcohols or tert-aliphatic alcohols are heated in DMSO at 160-185° C for 9-16 hours, dehydration produces
olefins in 70-85% yields (405), e.g.
OH
PhCHCH 2CH 3
DMSO
o
PhCH=CHCH3
160 C
16 hrs.
79%
2,2-Dimethyl-3(2H)-furanone can be obtained by dehydrating the corresponding 5-hydroxy compound on heating in DMSO (4755):
O
O
DMSO
HO
O
O
2-Methoxy-4,5-dimethylstilbene is obtained by heating 2-methoxy-4,5-dimethylphenylbenzylcarbinol in DMSO (9605):
61
OCH3
OCH 3 OH
Ph
DMSO
CH 2Ph
150oC
H 3C
9.5 hrs
CH 3
80%
H3C
CH 3
One of the key features of the stereoselective and regioselective total synthesis of two naturally occurring fungitoxic hydroquinones (±)zonarol and (±)-isozonarol is the dehydration of a tertiary alcohol to an alkene without rearrangement (9780):
HO
DMSO
H
77%
155oC, 16 hrs
H
In some cases, the dehydration is achieved in DMSO in the presence of an inorganic acid. Thus, the lactonization of a hydrolyzed
terpolymer can be carried out by reacting the polymer in the presence of a very small quantity of concentrated sulfuric acid in DMSO
(2265):
H3 C
HO2CHO2C
HO
H2SO4, DMSO H3C
CO2H
CH2OH
o
65 C, 100 hrs
HO
HO2C
CO2H
O O
Potassium hydrogen sulfate in DMSO is an effective medium for elimination of water from some intermediate hydroxy derivatives in the
preparation of various C 19 analogs of retinoic acid (4235):
R
KHSO 4 , DMSO
R
140-160oC
OH
18-40 min
Dehydration of 4-(1 -hydroxyethyl) biphenyl in DMSO in e presence of a small amount of potassium hydrogen sulfate and hydroquinone
gives p-phenyl-styrene (7867):
KHSO 4 , DMSO
OH 190C
several hours
82%
Dehydration of a diol can also be accomplished by using the triethylamine-sulfur trioxide complex in DMSO (7080):
OH
OH
Et3N / SO3, DMSO
15oC, 15 minutes
O
ISOMERIZATION REACTIONS
These are base-catalyzed reactions that convert olefins and other unsaturated compounds into molecules with different atomic
arrangement. Included are also racemization reactions: the conversion of half a given quantity of an optically active compound into one
enantiomer.
1. Acetylene Isomerization
The enhanced rate of base catalyzed isomerization in DMSO can be used to control the direction of a cyclization of acetylenes (600).
When propargyloxyethanol is cyclized in DMSO in the presence of sodium hydroxide, 2-vinyl -1,3-dioxolane and 2-methyl-l,4-dioxene
are the major products (101):
62
HC CCH2OCH2CH2OH
O
DM SO
NaOH
H2C C CHOCH2CH2OH
O
O
HC COCH2CH2OH
O
Treatment of an acetylenic compound with potassium tert-butoxide in DMSO gives the corresponding allenic compounds (2239):
R C C CH(A)-R'
R = Alkyl or phenyl,
R’= H, alkyl or phenyl,
t-BuOK, DMSO
30 oC
H
R C C C(A)-R'
A=Alkoxy, phenoxy, alkylthio, phenylthio, dialkyulamino, etc.
3-Phenylpropyne undergoes in DMSO a dimsyl ion-catalyzed isomerization with very little H-D exchange with the solvent (2987):
D 2CSOCD 3, (CD 3 )2 SO
PhH2 CC CH
PhHC C CH 2
4-Alkoxy-4-alkyl-1 -t-butoxy-2- butyne, when heated with catalytic amounts of potassium t-butoxide in DMSO, is isomerized to allenic
diethers (4257):
t-BuOK , DMSO R'
R'
C CCH2OtBu
C CHOtBu
RO
RO
50-78%
Similarly, 3-alkoxy-l -phenylpropynes are isomerized in DMSO under the catalytic influence of potassium tert-butoxide to give 3-alkoxy-1
-phenylallenes (4258):
Ph
R
R t-BuOK , DMSO
R
Ph
C
OC2H 5
O
40-67%
PhHC
OC2H5
H
The rates of base-catalyzed isomerization of a series of 1,3,3-triphenyl- prop-1-yne and [3-2H]-1,3,3-triphenylprop1-yne, have been
measured in aqueous DMSO containing tetramethylammonium hydroxide and give linear correlations with the acidity function for the
medium (5864).
Pure 2-alkynes are obtained upon heating 1-alkynes with sodamide in DMSO (6510):
NaNH 2, DMSO
R
CH 3
RH 2C
CH
o
65-70 C, 21 hrs.
90-94%
R=alkyl
2. Allyl Group Isomerization
The isomerization of allyl ethers to propenyl ethers occurs 1000 times faster in DMSO than in dimethoxyethane and 10,000 times faster
than in dimethoxyethane-t-butanol mixtures (481). This facile isomerization of allyl to easily hydrolyzed propenyl groups.enables the use
of allyl groups as blocking agents (10043). For example, 9-allyladenine is isomerized with potassium t-butoxide in DMSO to the propenyl
compound which is then easily hydrolyzed to regenerate the amino group (941):
N
N
t-BuOK , DMSO
o
N
N
N
N
100 C, 20 min.
82%
N
N
The allyl group of a glycoside can be isomerized to the prop-1 -enyl group by the action of potassium t-butoxide in DMSO, without
affecting phenyloxazine group (8951):
O
O OCH CH
R
OCH
R
2
t-BuOK
,
DMSO
CHCH3
CH
2
O
N
20 oC, 26 hrs.
O
N
77%
Ph
Ph
3. Diene, Triene Isomerization
Unconjugated dienes can be converted to the conjugated isomers by treating them with a strong base in DMSO. Thus, the treatment of 2bromo-1,3-cyclohexadiene (I) with potassium t-butoxide in DMSO yields a mixture of 79% 1-bromo-l,3-cyclohexadiene (II) and 21 % of I.
63
The difference in free energy between I and II appears to be the result of greater conjugation of bromine with cyclohexadiene system in 11
(596):
Br
Br
t-BuOK , DMSO
75oC, 8 hrs.
II.
I.
Several unconjugated dienamines on treatment with potassium t-butoxide in DMSO produce the conjugated dienamine by a pivoting of
the double bond around the carbon carrying the nitrogen atom (4018):
N
N
OCH3
OCH3
t-BuOK , DMSO
2-Methyl-1 -(tetramethylcyclopropylidene)propene is isomerized with potassium t-butoxide in DMSO to give 2 methyl-3(tetramethylcyclopropylidene)propane (4126):
CH3
CH3
H 3C
t-BuOK , DMSO H3C
CH3
CH3
C
o
CH3
100
C
,
2hr.
CH
3
H 3C
CH3
64%
CH3
Unsaturated fatty acid esters containing conjugated double bonds are manufactured by isomerization from the esters with
unconjugated double bonds by heating them with alkali metal alkoxides in DMSO (8906).
Steroids have been isomerized with a base in DMSO (3272)(2323). Thus, 19-hydroxy- ?
ketones by treatment with sodium methoxide in DMSO (4311):
HOH2C
O
NaOCH3 , DMSO
4,6
-3-keto steroids are deconjugated to ? 4,7 -3
HOH2C
room temp.
several min.
O
Sodium methoxide catalyzed deconjugation of cholesta-1,4-6-trien-3-one in DMSO to cholesta-1,5,7-trien-3-one is a key step in a
reported route to 1- a -hydroxy-vitamin D 3 (10048).
1,3,6-Octatrienes and 1,3,7-octatrienes are isomerized to 2,4,6-octatriene in 70-85% yields with hydroxide bases in DMSO (3379).
4. Olefin Isomerization
The isomerizations of simple alkenes (e.g. pentene-1,hexene-1) with potassium t-butoxide do not occur in tert-butanol, THF or 1,2dimethoxyethane. However, in DMSO with potassium tert-butoxide as the base, 1-olefins can be converted to 2-olefins, e.g. 2methylpentene to 2-methylpentene-2 (579):
H3C
CH3
t-BuOK , DMSO
H3CH2CHC
H3CH2CH2C
CH3
S-(2-propenyl)-L-cysteine is isomerized to cis-S-(1 -propenyl)-L-cysteine by reaction in potassium tert-butoxide and DMSO (1001):
t-BuOK , DMSO
H2C CHCH 2SCH2CH(NH 2)CO2H
25oC , 18 hrs.
H3CHC CHSHCH 2CH(NH 2)CO2H
60%
a-Pinene can be converted to ß -pinene by using potassium hydroxide and DMSO (480)(7229):
KOH , DMSO
110-190 oC
0.5 - 6 hrs.
4-6%
64
Similarly, (+)-sabinine isomerizes to an equilibrium mixture of 91 % (-)- a-thujene and 9% (+)-sabinine under the influence of
potassium t-butoxide in DMSO (2998):
t-BuOK ,DMSO
90oC, 2 hrs.
(+)-sabinine
(-)-α-thujine
Isomerization of a mixture consisting of 17.4% 1 -methylcyclopropene and 81.3% methylenecyclopropane with potassium t-butoxide
and t-butanol in DMSO produces a 98% pure methylenecyclopropane (4262):
t-BuOK ,DMSO
50-60oC
70%
5. Racemization
In the racemization of saturated compounds by exchange of hydrogen at an asymmetric carbon, the rate of racemization correlates
well with the acidity function of the reaction system containing DMSO (944). Similarly, the base-catalyzed rate of hydrogen-deuterium
exchange correlates well with the racemization rate (1501). In solvents of high dissociating power which are not proton donors, e.g.
DMSO, the carbanion (obtained with potassium t-butoxide) is long enough lived to become symmetrically solvated, and electrophilic
substitution gives a racemic product (1161).
A variety of active functional groups can be attached to the saturated asymmetric carbon atom.
a) Alcohols
When optically pure tertiary alcohols with an asymmetric carbon atom are treated with a strong base in DMSO, the predominant
steric course is racemization (1162)(2589).
b) Alkyl halides
The reduction of optically active tertiary alkyl halides with sodium borohydride in DMSO proceeds with racemization presumably via
an elimination mechanism (3519):
CH3
CH3
H3C
H3C
C2H 5
H3C
C2H5
H 3C
DM SO
H
Cl
8 NaBH4
CH3
H3C
CH3
H 3C
Racemic 2,7-dimethyl-octane
(-)-(R)-3-chloro-3,7-dimethyloctane
c) Amides, amino acids
D- a -Acetamide- a -vanillylpropionitrile is racemized using sodium cyanide as the base and DMSO as the solvent to give 96-97%
pure DL- a -acetamido- a -vanillylpropionitrile (7772)(7984):
H3CO
H3C CN
NH CH
HO
3
O
Optically active N-acylamino acids are racemized nearly quantitatively by heating with DMSO (8418).
d) Esters
The racemization and solvolysis of (+)-methyl 1 -cyano-2, 2-diphenyl-cyclopropane carboxylate has been studied in DMSO and six
other solvents. In DMSO, racemization is the dominant reaction (6287).
e) Ethers
Potassium t-butylmercaptide in DMSO is a weaker kinetic base system than potassium t-butoxide in DMSO or than dimsyl sodium in
DMSO in the racemization of optically pure (-)-1-methoxyphenylethane (496):
H3CO
H
Ph CH
3
DM SO
B-
H3 CO
C CH
3
Ph
DM SO
H3CO
BH
Ph
CH3 + BH
Rate constants for racemization of (-)-4-biphenyl-methoxyphenylmethane in methanol-0-d-DMSO-d6 catalyzed by potassium
methoxide have been measured (2007).
65
f) Hydrocarbons
The results of H-D exchange and racemization of (-)-9-deuterio-9-methyl-2-trimethylammonium fluorene iodide in t-butanol-DMSO
catalyzed by tripropylamine are reported. Exchange (69%) and racemization (69%) take place
(5339):
H(D)
CH3
N(CH3)3 I
D-tetramisole or its 1 -tetramisole enantiomer is racemized in DMSO solution in the presence of a catalytically effective amount of
potassium hydroxide (10315):
S
N
Ph
N
g) Nitriles
Racemization of 2-methyl-3-phenylpropionitrile in DMSO can proceed 1,000,000 times faster than in tert-butanol in the presence of the
same base (434)(944).
The mechanism of base-catalyzed racemization of a-acetamidonitriles bearing no enolizable a-hydrogen has been studied in DMSO
and found to proceed via elimination and readdition of the elements of HCN (2013).
The base catalyzed racemization of 2,2-diphenylcyclopropylnitrile (1) has been studied in solvents containing various amounts of
DMSO. With sodium methoxide as the base and nitrile 1 as a substrate, the rate for racernization in 1.5 mole % methanol-98.5 mol %
DMSO is 3.6 x 108 times that observed in methanol (7282):
Ph
Ph
CN
-OCH 3 , DMSO Ph
H
(-) -1
Ph
H
CN
(+) -1
h) Sulfones
When the 2,2-dimethyl-1-phenylsulfonylcyclopropane is heated in DMSO for 6 hours at 175° C the material is 88% racemized (2035):
H3C
CO2 CH3
H3 C
SO2 Ph
C. OTHER REACTIONS IN DMSO ADDITION REACTIONS
These are additions of nucleophilic compounds to carbon-carbon double bonds, carbon-carbon triple bonds, carbon-nitrogen triple
bonds and others.
In a number of cases the use of DMSO improves the rate of addition of nucleophiles to olefins, such as acrylonitrile. The rate of
addition of the glycine anion to acrylonitrile in an aqueous buffer is increased 200-fold by adding an equal amount of DMSO to the
buffer (1233). Similarly, the cyanoethylation of methanol using potassium methoxide catalysis in methanol-DMSO occurs at a rate
greater than in several other aprotic solvents. The order of effectiveness of the solvents for this reaction is also the order of their
hydrogen bonding strength (1591).
a) Additions to acetylenes (carbon-carbon triple bonds)
The DMSO anion (dimsyl sodium ) adds to diphenyl acetylene to give a 95% yield of a cis-trans mixture of the expected
unsaturated sulfoxide (203):
Ph
CH 2SOCH 3 Ph
Ph
DM SO
PhC CPh + Na+ CH2SOCH3
+
room temp.
H
Ph
H
CH2SOCH 3
95%
When the addition is conducted at 40°C, the reaction consumes 2 moles of the DMSO anion with elimination of two methane
sulfenate groups to give 2,3-diphenyl-1,3-butadiene (203):
PhC CPh + Na+CH2SOCH3
DMSO
40 oC
CH2
Ph
Ph
28%
CH2
66
Ethyl phenylpropiolate reacts readily with dimethyloxosulfonium methylide to give 91 % of a stable ylide (217):
PhC
(H3 C)2SOCH2
CO2 C2H5
HCO2C2 H5
PhC C
SO(CH3)2
91%
The addition of alkoxides to triple bonds in DMSO has been examined in structures where the intramolecular addition can
occur(600)(101)(429). The rapid rearrangement of the triple bond to the allenic compound seems to precede the cyclization (600):
N
CH2CH2OH NaOH , DMSO
C
N
CH3
CH2CH2OH
O
DMSO
N
CH3
CH3
Dinitrophenylhydrazine reacts with dimethylacetylenedicarboxylate in DMSO-methanol to yield a 1:1 adduct which exists as an imineemamine tautomer (3387):
CO 2CH 3
CO2CH3
CH2 CO2CH 3
DMSO
PhNHN
PhHNHNHC
PhNHNH2
+
room temp. , 15 hr
CO 2CH3
CO2CH 3
53%
CO 2CH 3
The reaction of alkynes with sodium azide in DMSO, followed by hydrolysis, affords 1,2,3-triazoles (3456):
R
R'
C
C
DMSO
N
N
N
11-54%
+ NaN3
RC CR'
DMSO has been one of the solvents studied in the reaction of 1 -propyl-sulfones and sulfoxides with ethylenimine. The greatest amount
of trans product (cis addition) is formed in DMSO. This may be explained on the basis that DMSO can stabilize the zwitterionic
intermediate best (3660):
H3 CC CSO 2 C2 H5 +
DMSO
NH
H3 C
room temp.
6 hrs
N
SO 2 C2 H5
H3 C
H
trans 84%
N
H
SO 2 C2H5
cis 16%
b) Additions to olefins (carbon-carbon double bonds)
Aliphatic conjugated dienes add the dimsyl ion in DMSO to give sulfoxides. These unsaturated sulfoxides isomerize spontaneously and
eliminate methanesulfenate upon continued warming in the strongly basic medium to produce the overall effect of methylation (411):
+ H2CSOCH3
DM SO
SOCH3
+B-
SOCH3
55oC
BH
β-elimination
+ H3CSO50%
Although the yields of the aliphatic dienes are 50% or less, the yields using polynuclear aromatic compounds or some heterocyclic
compounds, such as quinoline, are high (202):
CH3
+ H2CSOCH3
N
DMSO
70o C, 4 hrs.
N
96%
67
The dimsyl ion also adds to aryl conjugated olefins, such as styrene or 1,1-diphenylethylene, in DMSO to give the corresponding methyl 3arylpropyl sulfoxides in almost quantitative yield (423):
DMSO
Ph2C CH2 + H2CSOCH3
Ph2CCH 2CH2SOCH 3
25oC
Ph2CHCH2CH2SOCH3 + H2CSOCH3
One stage sequential double methylation of the C=C bonds in stilbene, 2-methylstilbene and 4,4'-dimethoxystilbene with the dimsyl ion in
DMSO leads to methyl diarylbutyl sulfoxides (7234):
CH3
CH3
Ph
+
Ph
DMSO
2H2 CSOCH3
CH2 CH2SOCH 3
Kinetic rate measurements of the alkoxide catalyzed addition of methanol and ethanol to methyl esters of acrylic and methacrylic acid
have been investigated in the mixed solvent alcohol-DMSO (3249).
1-Alkenecarbonitriles react with aromatic or heteroaromatic aldehydes in DMSO under the catalytic influence of cyanide ions to give ?oxonitriles (6172)(7582):
O
R"
R" CN-, DM SO
RCHO + R'HC
R
CN
CN
R' 54-91%
Alkyl esters of a , ß - and ß , ? -unsaturated carboxylic acids can be carboxylated at the a- or ß - position using sodium phenoxide in
DMSO (3506):
H2C
H3C
NaO2CH2C
CO2CH3
CO 2CH3
PhO
,
DMSO
or
or
+ CO2
CO2CH3
CO2CH3
H3C
25oC, 3 hrs
CO2Na
Sodium azide adds to a , ß -unsaturated nitro compounds in DMSO to form 1,2,3-triazoles (4452):
RPh
NO2 + NaN3
DM SO
room temp.
RPh
N
N
H
N
60%
Phenacyl bromide and its derivatives in the presence of zinc or a zinc-copper couple undergo anti-Markownikow additions to terminal
olefins (6627):
Zn-Cu , DMSO
H2 C Ar2
X-PhCO(CH2)2CHAr2
X-PhCOCH2Br +
140oC
54%
Phenacyl bromide in DMSO in the presence of the zinc-copper couple also adds to conjugated enynes and dienes (7536).
When olefins are treated with N-bromosuccinimide in DMSO containing a small quantity of water, the corresponding bromohydrins can be
obtained after a short reaction time in high yields (705)(4026)(4817):
Br
H2O , DMSO
+ BrN
o
20 C , 15 min.
OH
78%
A variety of alkylaromatic compounds undergo nucleophilic addition to conjugated olefins (3384). Particularly when the reaction is
performed in dipolar aprotic solvents, using potassium t-butoxide as a catalyst. The effectiveness of the solvents decreases in the
following order. DMSO, H MPA, N-methyl-2-pyrrolidone, DMF, sulfolane, tetramethylurea (4339).
68
c) Additions to nitriles (carbon-nitrogen triple bond)
The reaction of sodium azide with nitriles, such as benzonitrile, occurs readily in DMSO to give 5-phenyl tetrazole (550):
NH4Cl, DMSO
PhCN +
N
N
N NH
87%
Ph
NaN3
123-127oC, 7 hrs
The reaction of anthranilonitrile with sodium hydride in DMSO yields 4-amino-2-(2-aminophenyl)quinazoline (8576):
R
CN
NH2
NaH , DMSO R
0oC, 3hrs
R
CN
R
CN
+
NH2
NH2
DM SO
25oC, 21hrs
R
N
N
NH2
NH2
nearly quantitative
R= H orBr
Phthalodinitriles react with dicyandiamide in DMSO in the presence of basic compounds, such as potassium hydroxide, to
produce phthalo-bis -guanamines (8008):
NH2
N
CN
H
+
CN
2H2N
CN
NH
N
N
KOH, DM SO
85oC, 3hr
NH2
97%
N
H2N
N
N
NH2
d) Additions to isocyanates
The reactions of organic isocyanates and diisocyanates are catalyzed by DMSO, and they run at good rates in this solvent
(392)(312)(1360). Thus, diisocyanates react in DMSO with active hydrogen compounds such as dihydrazides (450), polyols
(449), or even with the hydroxyl groups of carbohydrates (cellulose) (443). In the last instance, DMSO is also used as an
effective swelling agent for cellulosic rayon fibers.
Diisocyanates, such as bis(4-isocyanatophenyl)methane or 2,2-bis(4-isocyanatophenyl)propane, react with ethylene glycol in
DMSO. Polyurethane filaments can then be spun from the reaction mixture (1880):
+ HOCH2CH2OH
NCO
O
a ketone
N
N
H
H
n
Dry DMSO is inert to alkyl or aryl isocyanates but it does react with isocyanates having electron withdrawing groups such as
acyl (714) or sulfonyl (308)(391).
A number of synthetic polymers containing sugar residues, such as D-cellobiose (10116)(10439) and a , a -trehalose (10123),
have been prepared by direct addition polymerization of the carbohydrate with diisocyanates, such as 4,4'methylenedi(phenylisocyanate) in DMSO.
CONDENSATION REACTIONS
These are mostly specific reactions (e.g. aldol condensation, Mannich reaction) in which two or more molecules combine,
usually with the separation of water or some other simple molecule.
Most of the ordinary reactions of carbonyl compounds can be accomplished in DMSO. Good results are often obtained either
because of the greater solubility of generally insoluble reactants or because of enhanced reactivity of nucleophiles.
a) Aldol-type condensations
Alkyl aryl ketones react easily and at a high rate with paraformaldehyde in DMSO in the presence of base to yield
hydroxymethyl compounds. The high reaction rates may be attributed to the high reactivity of the anionic catalyst in the DMSO
medium (1099). Thus, 1-indanone and formaldehyde react rapidly in DMSO to yield 2,2-bis(hydroxymethyl)-1-indanone:
OCN
DM SO
O
OH2 CH2CO
O
O
KOH, DMSO
room temperature
5 min.
CH2 OH
CH 2OH
70%
Fluorene and o- and p-nitrotoluene react similarly with paraformaldehyde in an aldol like addition in DMSO under the
influence of a strong base to give hydroxymethyl compounds (1100).
69
Racemic 2-(o-formylphenoxy)propiophenone can be prepared in 79% yield from equivalent amounts of a sodium salt of salicylaldehyde
and 2-bromopropiophenone in DMSO. When the reaction product is kept in DMSO in the presence of quinine, two optically active
diastereomeric ketols result (5613):
H
CHO
ONa
O
+ H 3C
DMSO
Ph
Br
CHO
DMSO
Ph
OC
79%
CH 3
OH
Ph
OC
CH3
O
O
The reaction of 1-hydroxy-2,2,5-trimethyl-3,4-hexadione with paraformaldehyde in DMSO in the presence of potassium hydroxide gives
1,6-dihydroxy-2,2,5,5-tetramethyl-3,4-hexadione (6028):
O
O
O
O
KOH, DM SO
+
2HCHO
o
20 C, 24 hrs
HO
OH
85%
2-Carbomethoxycyclohexanone condenses with 3-pent-2-one in DMSO in the presence of sodium methoxide to give methyl 4-methyl-1
(9)-octal-2-one-1O-carboxylate (4048):
H3CO2C
+
O
CO2CH3
NaOCH3, DM SO
29oC
O
O
The reaction of pentafIuoracetophenone with methyl benzoate in the presence of sodium hydride in DMSO is the best way to the
diketone (3376):
NaH, DMSO
C6 F6COCH3
C6F6 COCH2
PhCO2 R
C6F 6COCH2COPh
35oC, 24hrs
60%
b) Ester condensation
The esters of carboxylic acids react with the dimsyl ion in DMSO to yield ß -keto sulfoxides (639)(1651):
O
RCO2R' + 2H2CSOCH3
RCOCHSOCH3
H
SOCH3 + R'O- + DMSO
R
This condensation reaction has found a fairly wide application in the synthesis of useful intermediates. Thus, a number of benzoic acid
esters can be reacted with the dimsyl ion in-DMSO to give the corresponding ß -keto sulfoxides (9150):
OCH3
H3CO
O
DMSO
O
H3CO
CO2CH3+ 2H2CSOCH3
OCH3
S
20-25oC, 0.5 hr
H3C
OCH3
H3CO
70%
Ethyl salicylate reacts with 3.2 equivalents of dimsyl ion to give the ß -keto sulfoxides (9196):
O
CO2C2H5
+ 2H2 CSOCH3
OH
O
S
DMSO
OH
CH3
92%
A number of ß-keto sulfoxides have been prepared by condensing the dimsyl ion with substituted phenyl or naphthyl esters
(9249)(9402). Thus, ethyl 1-hydroxy-2-naphthoate reacts with the dimsyl ion to give 3'-hydroxy-2-(methylsulfinyl)-2'-acetonaphthone
(9244):
OH
OH O
O
CO2C2H5
+ 2H2CSOCH3
S
CH3
64%
70
Ethyl isovalerate gives methyl sulfinyl methyl isobutyl ketone (9825):
O
DMSO
(H3C) 2CHCH 2CO 2C 2H5 + H 2CSOCH 3
0 oC
O
(H3C) 2CHCH 2CCH 2SCH 3
1/2-1 hr.
The preparation and synthetic applications of ß-keto-suIfoxides have been reviewed (4820)(8529).
Symmetrical ß -diketones are readily prepared by reacting methyl esters with methyl ketones in DMSO with sodium hydride as the base
(193) :
O
DMSO
RCOCH3 + RCO2CH3 + 2NaH
O
CR
CH 2CR
75-83%
The yield is increased from 36% to 83% by using sodium hydride in DMSO instead of sodium methoxide in toluene.
In the presence of zinc-DMSO, 2,2,2-trichloroethyl esters of a -substituted ß -keto acids react stereospecifically at the a -carbon to the
ester carbonyl with aldehydes to give aldols in good yields (8833):
O
C
R
O
R'
CH
OH
Zn, DMSO
+ OHCR"
25oC
CO 2CH 3CCl 3
R
48-92%
CHR"
R'
Cyclohexanediones -1,3 are prepared in good selectivity by reacting an a , ß-unsaturated carboxylic acid ester with a ketone in the
presence of a strong base in DMSO (8717):
CH 3
O
NaOCH 3
H2C=CHCO 2CH3 + CH3COC2H 5
50oC, 1/2 hr.
O
c) Dieckmann condensation-cyclization
The Dieckmann condensation of dimethyl-l -methylcyclohexane 1,2-diacetate with sodium hydride in DMSO furnishes a crystalline keto
ester (6593):
CO 2CH3
CO 2CH3
NaH, DMSO
CO 2CH3
85oC
O
4 hrs.
CH3
CH3
68%
Reaction of diethyl ?-ketopimelate with an excess of methylenetriphenylphosphorane in DMSO provides for the introduction of an
exocyclic methylene group and subsequent Dieckmann condensation to the carbethoxycyclohexanone (6648):
CH 2
O
+Ph 3PCH 2, DMSO
C 2H5O 2C
CO 2C2H5
60%
CO 2C 2H5
O
71
d) Mannich reaction
A ß -keto carboxylic acid reacts with formaldehyde-piperidine hydrochloride in DMSO to give the corresponding a –methylene ketone in
excellent yield (6463)(8888):
O
O
O
DMSO
+ NH2 Cl
20oC
2 hrs.
+ HCHO +
O
O
O
CH2 N
CO2H
65%
HCl
CH2
The first step in the reaction is probably decarboxylation. The Mannich reaction product is most likely formed, but it loses piperidine
hydrochloride in the highly polar reaction medium.
The "Mannich reagent", dimethyl (methylene)ammonium iodide, reacts with enol borinates in DMSO-THF to provide excellent yields of ß dimethylamino ketones (6671):
O
CH 3
(R) 2 BO
R
DMSO-THF
CH 3
+
N IR'
N
Room temp.
80-100%
3 hours
CH 3
R'
R
CH 3
e) Michael condensation
The reaction of methyl a-bromo- ß-methoxypropionate (I) with sodium nitrite in DMSO in the presence of phloroglucinol gives dimethyl
a -methoxymethyl- a , a '-dinitrogluturate (IV), which is formed from methyl a - nitro - ß cnethoxypropionate (II) and methyl a nitroacrylate (III) by Michael addition (664):
H3COCH2
CHCO2 CH3 + NaNO2
phloroglucinol.
DMSO
H3 COCH2
Br
CH2
-MeOH
NO2
II
I
C
CHCO2 CH3
CO2CH3
+ II
H3 COCH2
O2 N
III
CO2CH3
H2
C
C
CHCO2CH3
NO2
NO2
IV
Double Michael reaction of 3-methyl-4-methylene-cyclohex-2-enone with dimethyl 3-oxoglutarate in DMSO in the presence of potassium
fluoride as a catalyst gives a mixture of the stereomeric diketodiesters (9746):
O
CO2CH3
KF, DMSO
+ H2C
OH
O
CHCO2CH2 CH2OH
55-60oC
CO2 CH3
2 days
CH2
Michael addition of carbazole to 2-hydroxyethyl acrylate in DMSO in the presence of 1,8-diazobicyclo[5.4.0]-7undecene (DBU) takes
place under mild conditions (10091):
DBU, DMSO
+ H 2 C=CHCO2 CH2 CH 2OH
N
H
room temp.
48 hours
N
CH 2CH 2CO 2CH 2 CH2 OH
Michael-type polyaddition of dithiols to divinylsulfoxide in DMSO leads to the formation of poly(sulfinylethylene-thioalkene (or
arylene)thioethylene)s (10443):
72
Et3N, DMSO
H2C
CH-SO-CH=CH2 + HSRSH
[CH2CH2-SO-CH2CH 2-S-R-S]n
60o
12hrs.
f) Reformatsky reaction
Bromonitriles, when treated with zinc in DMSO-THF, yield an intermediate organozinc compound. ß - Hydroxynitriles are then prepared
from this intermediate and aliphatic aldehydes and ketones (4767):
O
R
R
DMSO-T HF
R'
C
C+Zn
R'
Br
"R
CN
C
C
R'"
R'
C
C
R'"
"R
ZnBr
CN
OH R
30-66%
g) Thorpe-Ziegler condensation
1,4-Dinitriles, which can be prepared from dihalides or ditosylates and sodium cyanide in DMSO, can be cyclized directly to ß-enamino
nitriles in very high yields (477)(6163):
CN
OTs
DM SO
CN
+ NaCN
OTs
95oC
1 hr.
NaH, DM SO
NH2
95oC
1 hr.
CN
92%
The cyclization of 1,2-di-(cyanomethoxy) benzene with dimsyl ion (sodamide + DMSO) in DMSO produces 3-amino-4-cyano-2H-1,5benzodioxepin (8690)(9145):
CN
OCH2CN
O
H2CSOCH 3, DMSO
NH2
room temp.
3 hours
OCH2CN
92% O
h) Ullmann-type condensations
lodofluoroalkanes react with aryl iodides in DMSO in the presence of copper to give arylfluoroalkanes (5185)
(7293):
I
R'
Cu, DMSO
+ IR'
100-150 oC.
R
R
R = CF3, n-C3F7 , etc.
45-70%
i) Wittig reaction
The reaction of a tertiary phosphine (usually triphenylphosphine) with an alkyl halide to yield a phosphonium salt can be done in DMSO
(4669). DMSO also seems to be a good solvent for these salts. In these phosphonium salts, the a C-H bonds are sufficiently acidic
(5551) for the hydrogen to be removed by a strong base in DMSO, e.g. an organolithium compound (4110), sodium hydride or the dimsyl
ion (8360), to produce a phosphorus ylide (a phosphorane), the so-called Wittig reagent. Subsequent reactions of these ylides with
aldehydes, ketones or hemiacetals in DMSO offer a useful synthesis for olefins. The overall reaction can be written as follows
(49)(240)(5551):
Ph3P + RCH 2X
DMSO
Ph3P + CH 2RX -
+ - R2CO, DMSO
DMSO
Ph3P-CHR
R2C=CHR
base
As mentioned above, the Wittig reaction converts carbonyl compounds to olefins. Thus, the reaction of formaldehyde and the
phosphorane derived from 1 ,5-bis(triphenylphosphoniomethyl)naphthalene dibromide in DMSO gives 1,5-divinylnaphthalene (7641):
73
+
CH2 PPh3Br-
DMSO
+ HCHO room temperature
overnight
CH2 SOCH 3, DMSO
room temperature
2.5 hours
CH 2PPh3 Br
CH=CH 2
CH=PPh3
-
64%
CH=CH 2
CH=PPh 3
Ketones react with phosphoranes in a way similar to aldehydes. Verbinone with methylidenetriphosphorane in DMSO yields
methylenedihydroterpine (7476):
CH2
O
n-BuLi, DMSO
+
Ph3 P=CH2 +
Ph3 PCH3I-
DMSO
reflux
overnight
Lactols (hemiacetals) can also be reacted with a Wittig reagent (7691). Treatment of a lactol with a Wittig reagent derived from 5triphenylphosphovalerate ion in DMSO gives the corresponding hydroxy acid (7729):
OH
OH
O
+ Ph3P=CH(CH2)3CO2H
CH2CH (CH2) 3CO 2H
DMSO
R
R
It has also been found that aromatic and aliphatic esters can be directly converted to the corresponding isopropenyl compounds by
reaction with methylenetriphenylphosphorane in DMSO (10078):
CHR"
O
R
C
OR' + 4PH3P=CHR" +3Na+CH2-SOCH3
DMSO
R
C
CH 2R"
OXIDATION REACTIONS
These are reactions in which oxygen combines chemically with another substance or reactions in which electrons are transferred from
one substance to another. DMSO in these reactions, with a few exceptions, is a solvent and not a reactant, i.e. it gets neither reduced
nor oxidized.
Many different reactions using oxygen have been conducted in DMSO, such as autoxidation (also chemiluminescence),
dehydrogenation, hypohalite reactions, lead tetraacetate oxidation, silver compound oxidations, superoxide and peroxide oxidations and
others not discussed here (e.g. electrooxidation, periodic acid oxidations, manganese dioxide oxidations, sulfur dioxide oxidations).
a) Autoxidation
The base-catalyzed oxidation of a number of compounds by oxygen in DMSO-t-butanol mixtures has been studied extensively.
Formation of the carbanion of the substrate usually precedes the oxidation. The rate of carbanion formation and oxidation increases as
the DMSO content is increased (728).
In the solution DMSO-t-butanol-potassium t-butoxide, a number of hydrocarbons can be oxidized easily. Thus, triphenylmethane
reacts with oxygen in the above system to form triphenylcarbinol (479):
DMSO-t-BuOH-t-BuOK
Ph3CH + O2
room temp.
20 min.
Ph3COH
96%
Aniline under the above conditions gives azobenzene (469):
DMSO-t-BuOH-t-BuOK
PhNH2 + O2
PhN=NPh
room temp.
1 hr.
Ketones in DMSO-potassium t-butoxide are oxidized to semidiones (1787):
74
O
H
.
-
H
t-BuOK, DMSO
O + O2
O
R
R
Some ketones can also be oxidized to the carboxy compounds (9707).
When nitrotoluenes are oxidized in DMSO-potassium t-butoxide, dimers or acidic products can be formed (568). Thus, the autoxidation of
o- and p-nitrotoluene in DMSO under basic conditions result in the formation of 1,2-di(nitrophenyl)ethanol, presumably via the
corresponding nitrobenzaldehydes (4812):
OH
CH3
KOH, DMSO
+ O2
O2N
NO 2
NO 2
The above dimers can be further oxidized to ketones, or dehydrated to nitrostilbenes (4812).
The autoxidation of 1- and 3-arylpropenes has been induced with the DMSO-t-butanol system containing potassium t-butoxide. The
autoxidation of safrole gives piperonylic acid. Without DMSO, no oxidation takes place (1140):
O
DMSO-t -BuOH-t -BuOK
CO2H
O
+ O2
O
42%
O
In the presence of alkali metal hydroxides, it is possible to oxidize various substituted methanes, such as a, a-diphenyl-2-pyridenemethane,
to the corresponding alcohols using air or oxygen and DMSO as the sole solvent (6971):
R
R
NaOH, DMSO
R'
C
H+O2
R'
C
R"
OH
R"
1,2,5,6-Dibenzanthracene and s everal other aromatic hydrocarbons are oxidized to the corresponding quinone derivatives in basic
DMSO (5587).
Autoxidation of 1 -methyl-2-isopropyl-5-nitroimidozole in DMSO with air or oxygen in the presence of a base gives 2-(2-hydroxy-2propyl)-1-methyl-5-nitroimidazole (8867):
CH3
N
NO2
CH3
CH3
KOR, DMSO
C
CH3
N
NO2
+ O2
CH3
C
OH
CH3
N
N
Base catalyzed autoxidation of ethyl 2-cyano 3,3-disubstituted carboxylates in DMSO gives good yields of the 2-oxo esters (3662):
R
R'
C
R
CN
CHCO2C2H5+ O2
DM SO, t-BuOH, T-BuOK
R
O
R'C
C
CHCO2C2H 5
R
The system cobalt (II) and/or (III) acetylacetonate-t-butyl hydroperoxide has been used to initiate autoxidation of polyvinyl alcohol) in
DMSO (8043).
9,10-Dihydroanthracene can be oxidized to anthraquinone with oxygen in DMSO containing an inorganic base, such as sodium
hydroxide (2940).
75
b) Chemiluminescence
Chemiluminescence reactions are very similar to autoxidation. Both these reactions require oxygen and the presence of a strong base.
Chemiluminescence reactions can be classified as special autoxidation reactions that produce light emissions. As the basicity of
alkoxides and hydroxides is enormously enhanced in DMSO over the value of hydroxylic solvents, it has also been observed with
chemiluminescence reactions that the emission periods have been increased and the light intensities enhanced in DMSO containing a
base (1025).
A bright green light is observed on the treatment of a solution of 2,3-dimethylindoie and its hydroperoxide in DMSO with a base, e.g.
potassium t-butoxide or granular potassium hydroxide (2140)(2218):
CH3
CH3
CH3
+ O2
OOH
CH3
KOH, DMSO
N
base, DMSO
N
O
H
CCH3
+ light
N
H
CCH3
O
When DMSO, luminol, water and caustic solution are shaken in the presence of oxygen from air, an oxidation reaction produces
considerable bright blue-green light. The reaction sequence can be represented as follows (3241):
O
O
-
DMSO
NH
N
-
N
NH
NH2
DMSO
+ O2
+ 2NaOH
H2N
O
O
O
O
O-
N-
N2
+
N
NH2
O2
-
O
O
NH2
+ light
-
O
Some derivatives of luminol, containing methoxyl groups, are more efficient in chemiluminescence in DMSO solution than luminol itself
(1668).
The reaction of potassium cyanide with N-methylacridinium chloride in 90% DMSO-10% water produces Nmethyl-90-cyanoacridan. With
excess cyanide, the red N-methyl-9-cyanoacridanide ion is produced which, in the presence of oxygen, produces N-methylacridone and
potassium cyanate with light emissions (3653):
CN
+ KCN
O
KCN, DMSO
DMSO-H 2 O
+ O2
N
+
CH3 Cl-
N
CH3
+ HOCN + light
N CH3
The chemiluminescence emission spectra of two efficient chemiluminescent linear hydrazides in DMSO with potassium t-butoxide and
oxygen suggest that the corresponding acid anion is the light emitter (5116):
76
O
R
O
t-BuOK, DMSO
CNHNN 2
R
C-N -HNN 2
R
CNNH
O
O
t-BuOK, DMSO
O
O2, DMSO
R CN=N -
RC- + light
c) Other oxidations with oxygen
Carbonyl compounds can be manufactured by oxidation of olefins, such as ethylene, propylene, styrene, and cyclohexane, in waterDMSO mixture in the presence of a catalyst to give acetaldehyde, acetic acid, acetone, propanol, acetophenone and others (5800).
DMSO can be used as a catalyst component in the oxidation of olefins, e.g. DMSO can be a coordinate in complexes such as
Cu(ClO4)2(DMSO)4 , or Fe(ClO4),(DMSO)4, (9412).
3-Oxo- ?4-(19)-norsteroids react with oxygen in DMSO to afford 1,3,5-(10)-oestratrien-6-ones (5912):
+ O2
KOAc, DMSO
100-120oC
OH
4 hours
O
O
15-48%
The liquid phase oxidation of s-butanol with oxygen under pressure has been examined in various solvents using vanadium pentoxidemolybdenum trioxide catalyst While no reaction occurs in water, benzene, or chlorobenzene, the oxidation in DMSO at 125°C for 13 hours
converts 10.8% of s -butanol to methyl ethyl ketone with a selectivity of 89% (9434).
Terpenes can be oxidized with dry air in DMSO. Thus, a -longipinene is oxidized at 125-135°C to longiverbone as the major product
(9871), and p-mentha-1,4(8)- and -2,4(8)- dienes at 100 °C give p-methylacetophenone (9874).
In neutral solution, benzyl alcohols can be oxidized by oxygen in the presence of ultraviolet light to give the corresponding aldehydes
(737)(1118):
C6H5CH2OH + O 2
UV, DMSO
C6H5CHO + C 6H5CO 2H
room temp.
48.7%
12.6%
The oxidation of benzoin by cupric sulfate and oxygen in DMSO occurs to give a high yield of benzil (945):
O
O
CuSO4, DM SO
Ph
HO
+ O2
o
Ph
90-100
C
97%
Ph
1 hour
O
Ph
d) Dehydrogenation
In the dehydrogenation reaction, oxidation (i.e., the removal of hydrogen) can take place without the presence of oxygen.
Several platenoid metal catalysts in DMSO promote dehydration, disproportionation and dehydrogenation of diarylcarbinols (10422). The
dehydrogenation can be the main reaction when DMSO is used as the solvent instead of a -methylnaphthalene (8838):
RuCl2(PPh3)3 , DMSO
R2CHOH
R2 C=O + H2
Dihydroarenes, e.g. 1,2-dihydronaphthalene, can be converted into the corresponding aromatic compounds, e.g. naphthalene, by
deprotonation with potassium fencholate, followed by dehydration with fenchone (2-oxo-1,3,4-trimethylbicyclo [2.2.1 ]-heptane) (9707):
H
O-, DMSO
+
+
90o
H
OH
O
95%
77
5,7,4'-Trimethoxyflavanone, when heated with DMSO in the presence of a catalytic amount of iodine and concentrated sulfuric acid,
gives 5,7,4'-trimethoxyflavone in almost quantitative yield (10,000):
OCH 3
OCH 3
O
O
OCH 3
I2, H2SO 4 , DMSO
OCH 3
OCH 3
OCH 3
O
O
A solution of sodium dichromate and sulfuric acid in DMSO oxidizes primary alcohols to aldehydes and secondary alcohols to ketones. In
these oxidations, DMSO acts as a solvent and not as a reactant (7609):
R
Na 2Cr2 O7 , DMSO, H2 SO4
R
CH-OH
C=O
R
R
80-90%
e) Hypohalite oxidations
Halogenations with sodium hypohalites of alkyl - or arylamidines and isoureas in DMSO solution afford the corresponding alkyl-, aryl- or
alkoxy-3-halodiazirines in practical yields (843):
NH
R
NaOX, DMSO
R-C-HN 2
25-55oC
N
C
X
N
3-haloazirine, 60%
Oxidative cyclization of trifluoroacetamidine with hypochlorite and chloride ion in aqueous DMSO gives the corresponding diazirine
(8108):
NH
CF3
-OCl, LiCl, DMSO-H2O
F3 C-C-HN2
N
C
Cl
N
f) Lead tetraacetate oxidations
Polysaccharides, such as dextran and amylose, can be oxidized by lead tetraacetate in DMSO if 15-20% of glacial acetic acid is added
to prevent oxidation of the solvent. This oxidation proceeds at a rate which is several times faster than the periodate oxidation in
aqueous solution. Polysaccharides oxidized by lead tetraacetate contain free aldehyde groups. Oxidation follows the normal glycolcleavage pattern (615).
Oxidation of 1 -amino-3,4,5,6-tetraphenyl-2-pyridone with lead tetraacetate in DMSO gives the corresponding 5,5-dimethyl-Nsulfoximide, indicating that DMSO is an efficient trap for N-nitrenes (4987):
Ph
Ph
Ph
N
Ph
Ph
Ph
Pb(OAc)4 , DMSO
room temp.
O
1 hour
Ph
Ph
Ph
Ph
N
Ph
O
N
N
N:
N
Ph
DMSO
O
S(CH 3) 2
O
Similarly, lead tetraacetate oxidation of N-aminolactams in the presence of DMSO gives the sulfoximides in good yields (5846):
Pb(OAc)4, DMSO
R2N-NH2 + DMSO
H3C
R2N-N
S
O
H3C
Oxidation of aminonaphth[2,3-b]azet-2(1 H) -one by lead tetraacetate in DMSO leads to 2-naphthoic acid
(6243):
78
O
Pb(OAc)4, DMSO
CO 2H
NR
Treatment of a dicarboxylic acid (prepared from the Diels -Alder adduct of dimethyl - cyclobut-1-ene-1,2dicarboxylate with butadiene) with
lead tetraacetate in DMSO containing pyridine gives a product which is mainly bicyclo [4,1,0]octa-1(6),3-diene, with a small amount of
benzocyclobutene (7533):
CO 2H
Pb(OAc)4, DMSO, pyridine
+
CO 2H
g) Silver compound oxidations
A number of alcohols, e.g. methanol, ethanol, n-propanol, isoborneol, can be oxidized by argentic picolinate to yield the corresponding
aldehydes or ketones, i.e., formaldehyde, acetaldehyde, propionaldehyde, camphor. The rate of reaction is influenced by the solvent,
and the use of DMSO leads to a more rapid reaction (2915):
DMSO
R'RCHOH + 2Ag(pic)2
R'RC=O + 2Ag(pic) + 2 pic-H
40-70 oC
10-15 min.
66-80%
Oxidation of menaquinol-1 dimethyl ether with silver picolinate in DMSO gives the desired alcohol (4653):
OCH 3
OCH3
CH2OH
CH3 Ag++ picolinate, DMSO
80oC
30 min.
R
OCH3
R
25%
OCH 3
Reaction of 1,2-diphenyl-2-[(phenyl)methylamino]vinyl chloride with silver (II) oxide in DMSO gives benzil (5843):
Ph
Cl
PhMeN
Ph
Ag2O, DMSO
reflux
1 1/2 hr.
Ph
O
Ph
95%
O
In boiling nitromethane with silver tetratluoroborate, the yield of benzil is only 60% (5843).
Bromoalkyl formates are easily converted to protected secondary hydroxyaldehydes by treatment with silver tetrafluoroborate in DMSO
in the presence of triethylamine (7507):
OCHO
OCHO
AgBF4, DMSO, Et 3, N
H3C-CH-(CH 2)nCH 2Br
-5 to -20oC
24 - 120 hrs.
H3C-CH-(CH 2)nCHO
50-90%
The use of silver nitrate in DMSO on a 3-chloro-7-hydroxy-1 7-oxo-androstane accomplishes two purposes. It oxidizes the 7-hydroxy
group to the 7-oxo group, and it dehydrohalogenates the steroid (8340):
79
AgNO 3, DMSO
Cl
reflux
OH
O
52%
17 a-Ethynyl-17 ß-hydroxysteroids are converted quantitatively to the corresponding 17-ketones by treatment with excess silver
carbonate or silver oxide in DMSO (7460):
O
OH
C
C-R'
Ag2CO 3, DMSO
OR
Dimethyl esters of monoalkylated malonic acids and ß-keto esters are easily oxidatively dimerized by silver oxide in DMSO (8830),
e.g.:
CO 2 R'
R-CH
R'O 2C
Ag 2 O, DMSO
CO 2 R'' 70-80oC
R
CO 2R'
C
C
R
CO 2 R'
CO 2 R'
70-90 %
h) Superoxide and peroxide oxidations
Secondary amines are instantaneously oxidized to dialkylnitroxides by potassium superoxide in DMSO (6293):
DMSO
R2NH+O2-
-
R2N-O + OH
Alcohols are the major end products resulting from the reaction of alkyl halides and tosylates with an excess of potassium superoxide in
DMSO in a rapid process in which the C-O bond-forming step proceeds with inversion of configuration (8030):
C6 H13
C6H 13
H
C
X
KO2 , DM SO
25oC
75 min.
CH 3
X = Cl, Br, I, OTs
OH
C
H
CH3
With 1 -bromooctane, the yield of 1 -octanol is 63%.
Phenolic compounds are prepared by oxidation of aromatic hydrocarbons with organic hydroperoxides in the presence of boron oxide,
meta- or orthoboric acid ortheir lower alkyl esters, and DMSO. Thus, DMSO is added to a mixture of m-xylene, tetralin hydroperoxide and
boron oxide to give 38:62 ratio of 2,6- and 2,4-xylenol, dihydronaphthalene and tetralone (8658).
REDUCTION REACTIONS
These are reactions in which hydrogen is added or oxygen or a halogen is removed. DMSO can be either a solvent or a catalyst
component.
Although DMSO can be either oxidized or reduced, it is comparatively stable toward both changes and hence can be used as a solvent
for many oxidation-reduction reactions. In polarography studies using tetraethylammonium perchlorate electrolyte, the usable potentials
range from +0.3 volts anode potential to-2.8 volts cathode potential (both relative to the standard calomel electrode) (553)(772). In
general, the halfwave potentials for inorganic ions in DMSO are quite similar to those in aqueous solutions (553). However, a more
negative cathode potential is usable in DMSO as shown by the observation of the magnesium wave at -2.20 volts. Lithium metal is inert
toward DMSO (206). The electrodeposition of cerium cannot be accomplished in aqueous solution because the metal is too positive but it
can be deposited from a DMSO solution of cerium chloride (1744). The transfer of electrons between molecules of redox systems
sometimes occurs very readily in DMSO as observed for isotope exchange between ferrous and ferric perchlorates (1036)(923) and in
80
the base-catalyzed transfer of electrons between unsaturated organic molecules and their dihydro derivatives (722).
1. Reduction of Alkyl Halides and Sulfonates
a) Reduction with sodium borohydride
the selective substitution of hydrogen for primary, secondary or, in certain cases, tertiary halogen (or sulfonate) in alkyl halides without
reduction of other functional groups present in the molecule may be effected by reduction with sodium borohydride in DMSO
(2980)(3248):
R
R1
C-X
R
R
NaBH4, DMSO
11
R1
25-100oC
C-H
R
11
X=Cl, Br, I, tosylate
Sodium borohydride in DMSO is a convenient source of a nucleophilic hydride which may be used for the reductive displacement of
primary and secondary alkyl halides, or sulfonate esters (e.g. tosylates). The mildness of borohydrides allows a number of chemoselective
transformations without damage to groups (e.g. COOR, COOH, CN, NO2) normally affected by harsher reagents such as lithium aluminum
hydride (9783).
The reduction of optically active tertiary alkyl halides with sodium borohydride in DMSO proceeds with racemization, presumably via an
elimination-addition mechanism (3519):
BH3/H+, DMSO
NaBH4, DMSO
R(ene)
R-Cl
RH
4-Nitro-2-chloromethyl-1-isopropylbenzene can be reduced with sodium borohydride in DMSO in good yield (4602):
CH 3
CH2Cl
(H3C) 2HC
(H 3C)2HC
NaBH4, DMSO
room temp.
NO 2 3 1/2 hrs.
NO 2
82%
An iodo-tosylate can be reduced with sodium borohydride in DMSO to give one major product, a cyclopentadiene (6502):
CH 2I
CH 3
NaBH 4, DMSO
100 o C.
OTs 27 hrs.
In the above case, both reduction of the iodide and elimination of the tosylate take place.
Sodium borohydride in DMSO selectively reduces 2-chloro-4-chloromethyl naphthalene to 1-chloro-4methylnaphthalene (6785):
Cl
Cl
NaBH 4, DMSO
room temp.
2 hours
CH 2Cl
72%
CH 3
Sodium borohydride in DMSO-water reacts with a , a , a , a’, a’, a’-hexachloro-p-xylene to give an insoluble polymer (7205):
81
CCl 3
CCl 3
NaBH4, DMSO-H2O Cl
Cl
C
Cl
25 oC
Cl
C
Cl
C
Cl n
C
Cl
Cl
c) Reductions with chromous ion
Reduction of a, a-dichlorobenzyl benzyl sulfoxide to a mixture of diastereomeric a-chlorobenzylbenzyl sulfoxide can be carried out by
chromous ion in aqueous DMSO (6972):
O
Cl
O
S
Cl
CrCl2, aq. DMSO
S
room temp
Cl
Ar
Ar
Ar
Ar
The use of n-butanethiol and chromium (II) acetate in DMSO in the reduction of a 5 a-bromo-6 ß-hydroxysteroid permits the removal of
the bromine and the isolation of the 6 ß-hydroxy-steroid (6825)(6970):
Cr(OAc)2, n-BuSH, DMSO
OAc
OAc
Br
H
OH
OH
c) Reduction with dimsyl ion
Treatment of 8,8-dibromobicyclo[5,1,0]octane with dimsyl sodium in DMSO produces exo-8-bromobicyclo [5,1,0]octane (454)(3009):
H2CSOCH 3, DMSO
Br
Br
Br
H
d) Reductions with hydrazine
Hydrazine can reduce meso-1,2-stilbene dibromide in DMSO to a -bromostilbene and some bibenzyl (6509):
DMSO
PhCHBrCHBrPh + N2H 4
PhCH=CBrPh + PhCH 2CH2Ph
18%
66%
e) Reductions by electrolysis
Controlled potential electrolysis of 2,4-dibromopentanes in DMSO containing tetraethylammonium bromide (TEAB) gives cis - and transdimethylcyclopropanes and small quantities of 1-pentene, 2-pentene and n-pentane (4492)(6659):
H3 C
H3C
H3C
Br
Br
-
2e , TEAB, DMSO
Br
H3 C
Br
CH3CH 2CH 2CH=CH 2 + CH 3 CH2CH=CHCH
3
+
CH 3
+ CH 3(CH 2)3CH 3
2. Reduction of Carbonyl Compounds
Carbonyl compounds, aldehydes and ketones in DMSO can be reduced by electrochemical means or by Wolff-Kishner reduction of the
corresponding hydrazones.
a) Reductions with borohydrides
The kinetics of the reduction of acetone, pivalaldehyde, (H3C)3CCHO, and benzaldehyde by sodium borohydride and
tetramethylammonium borohydride have been determined in DMSO-water systems. The reactions obey 2nd order kinetics (8953):
4R2CO + BH4- + H2O
DMSO
R2CHOH + B(OH)482
The reduction product of benzaldehyde in DMSO is NaB(OCH2Ph)4, which is readily hydrolyzed to benzyl alcohol, PhCH2OH (8953).
When benzaldehyde is reduced in DMSO and DMSO-water mixtures of tritiated sodium borohydride, the reduction is accompanied by
the incorporation of tritium into the aldehyde group of unchanged benzaldehyde (8954).
b) Catalytic reduction
The mechanism of reduction of cyclic ketones by the system iridium(III) salt-sulfoxide-isopropyl alcohol has been investigated. With 4-tbutyl cyclohexanone, a 97% conversion to 4-t-butylcyclohexanol, with a cis/trans ratio of 1.50, can be achieved with DMSO as the
sulfoxide (4436):
IrCl3-i-Pr-DMSO
O
OH
97% conversion
An unusually selective hydrogenation of a , ß-unsaturated aldehydes to the unsaturated alcohols has been accomplished catalytically
under mild conditions using the iridium complex HlrCl2(DMSO)3 in isopropanol, the solvent being the source of hydrogen (9752):
HlrCl2(DMSO) 2
RCH=CHCHO + H 2
RCH=CHCH 2OH
c) Electrochemical reduction
The electrochemical reduction of carbonyl compounds, particularly ketones and diketones, has been studied in DMSO (2567)(3217).
The reduction of 1,3-diphenyl-1,3-propanedione in DMSO proceeds by an overall 0.5 electron process (5971):
OH
OH
O
4Ph-C=CH-C-Ph +2e
Ph
DMSO
Ph
O
H2
C
H2
C
C
C
C
OH
Ph
Ph
+
Ph2
OH
O
dimeric pinacol
C
O
H
C
C
Ph
enolate anion
d) Wolff-Kishner reduction
The Wolff-Kishner reduction, the reaction of hydrazones of aldehydes and ketones with a base to produce the corresponding
hydrocarbons, has been run in DMSO (495)(377):
Ph2 C=NNH 2
t-BuOK, DMSO
25o C
8 hours
benzophenone
hydrazone
Ph2CH 2 +N2
90%
diphenyl methane
The Wolff-Kishner reduction in DMSO has been carried out in the presence of potassium t-butoxide, dimsyl sodium, and other base
catalysts, and the activation parameters have been determined (8735). The Wolff-Kishner reaction mechanism in DMSO has been
reviewed (1942)(3048).
3. Reduction of nitroaromatics
The reduction of aromatic nitro compounds with sodium borohydride in DMSO initially produces the azoxy compounds which, in most
cases, are subsequently reduced to the corresponding azo derivatives and amines (4946), e.g.:
NaBH4, DMSO
Ph-N=N-Ph
PhNH2
azoxybenzene azobenzene
aniline
Ph-N=N-Ph
PhNO2
o
85-100 C
O
nitrobenzene
In the case of o-nitroanisole, 63% of o-methoxyaniline and 23 % of the azobenzene are produced.
Nitroaromatics are selectively hydrogenated in neutral media in the presence of precious metal catalysts and DMSO to produce Narylhydroxyamines in high yield. Thus, nitrobenzene in the presence of platinum on carbon and DMSO yields hydroxylamine and phenyl
aniline (5663):
83
Pt/C-DMSO
PhNO2 + [H]
PhNHOH+ PhC6H 4NH 2
ethanol
room temp.
86%
13%
Catalysts of noble metals on activated carbon can be subjected to the action of DM SO together with hydrazine or its derivatives. The
hydrogenation of 2-chloronitrobenzene in the presence of platinum on carbon and DMSO gives a high yield of 2-chloroaniline (8118):
Cl
Cl
NO 2
NH 2
+
Pt/C-DMSO
[H]
hydrazine
Similarly, the reduction of nitrobenzene with hydrogen over platinum oxide in alcohol (methanol or ethanol)sulfuric acid in the
presence of DMSO produces p-alkoxyaniline (9294)(9581):
NO2 +
[H]
PtO2, DM SO
OR
NH2
ROH-H2SO4
4. Reduction of C=C Systems
The electrochemical reduction of several aryl a , ß -unsaturated ketones, C 6H5CH=CHCOR, has been studied at mercury cathodes by the
techniques of polarography, controlled potential coulometry and cyclic voltammetry. Conditions have been established under which a
dimer of the a, ß-unsaturated ketones is formed by coupling at the ß-carbon atoms in good yields. A suitable medium for the reduction is
tetra-n-butylammonium perchlorate in DMSO with added lithium perchlorate (4253), e.g.:
H
Ph
COR
CH 2COR
75%
H LiCO4, DMSO-H 2O Ph
Ph
CH 2COR
R = t-butyl
Diimide, generated by the sodium metaperiodate oxidation of hydrazine in DMSO, is a particularly useful reducing system for olefins or
compounds which contain readily oxidized functional groups (4392), e.g. maleic anhydride can be reduced to succinic anhydride:
O
HC
C
HC
C
O
O
HN=NH, DMSO
H2 C C
O
H2 C C
O
95% O
A thiophene derivative is reduced the same way (4392):
SCH3
SCH3
HN=NH, DMSO
S
S
CO2 C2 H5
CO2C 2H5
Allylbenzene can be hydrogenated by chloro(DMSO)palladium complexes (5526):
PhCH2CH=CH2 + [H] (DMSO)2 PdCl2
PhCH2CH2CH3
In the presence of the same catalyst, 1 -pentene is converted to isomers more rapidly than without the catalyst and the bond migration of
the pentene is more rapid than its hydrogenation (5630).
Double bonds in some a, ß-unsaturated ketones are reduced by propen-2-ol in the presence of soluble iridium -DMSO catalysts (7031):
PhCOCH=CHPh
i-PrOH, H[IrCl 4(DMSO) 2]
73o C
PhCOCH2CH2Ph
95%
Acrylic acid and its derivatives can be dimerized in high yields by means of alkali metal amalgam in DMSO-water. Acrylonitrile gives
adiponitrile (4907):
84
Na amalgam, DMSO-H2O
2 CH2=CHCN
NC(CH 2)4 CN
95%
Diethyl fumarate, C 2H5O2CCH=CHCO2C2H5, can be dimerized by electrochemical reduction (7331).
SOLVOLYTIC REACTIONS
These are reactions in which the elements of water (also alcohols or amines) are added, usually with the formation of two new
substances.
1. Hydrolysis
The DMSO-water system has been used in many hydrolysis reactions. The rates of base catalyzed reactions usually increase as the mole
fraction of DMSO in the mixture increases, and the increase is particularly rapid above 0.7 mole fraction of DMSO
(336)(367)(369)(464)(726)(730). The opposite is sometimes true in the case of hydrolysis in the presence of acids. The rate of acid
hydrolysis decreases as the mole fraction of DMSO is increased, particularly above 25-30% DMSO (368). A similar decrease is seen for
the acid catalyzed hydrolysis of acetals (742) and the reaction of tert-butyl chloride with aqueous DMSO (431)(1028)(1521).
a) Aliphatic halide hydrolysis
The alkaline hydrolysis of alkyl halides has been studied in DMSO-water (329)(432)(2583)(4846). In the alkaline hydrolysis of methyl
iodide, DMSO exerts a strong accelerating effect. The rate of the hydroxyl ion catalyzed reaction in DMSO is up to 106-107 times the rate in
water (329).
The rate constants for the reaction of hydroxyl ion with benzyl chlorides in acetone-water decrease with increasing acetone concentration
while the rates increase with increasing DMSO concentration in DMSO-water (432).
The rate of alkaline hydrolysis of chloroacetic acid increases with increasing concentration of the organic component in acetone-water,
THF-water, dioxane-water and DMSO-water. However, the increase is greatest in DMSO-water (2583).
Alcohols can be prepared from alkyl halides in DMSO-water in the presence of a base. Thus, octanol is obtained from octyl chloride and
calcium hydroxide in DMSO-water at reflux (4846):
DMSO-H 2O
Octyl chloride +Ca(OH)2
reflux
4 hrs.
Octanol
92%
Solvolysis of 2-adamantyl bromide and a-chloroethylbenzene decreases with increasing DMSO content (2194)(3766)(2196).
The Diels -Alder adduct, obtained by reacting 5-methoxymethyl-1,3-cyclopentadiene with chloroacrylonitrile, is converted with aqueous
potassium hydroxide in DMSO to the anti-bicyclic ketone (3033):
H 3COH2C
H COH C
3
2
KOH, DMSO-H 2O
o
25-30 C
Cl
14 hours
O
CN
b) Aromatic halide hydrolysis
Aromatic halogens can be hydrolyzed from activated nuclei by aqueous bases in DMSO. The rate coefficients for the alkaline hydrolysis of
a series 1-halogen substituted 2,4-dinitrobenzenes have been measured in aqueous DMSO. These rates have been correlated with the
acidity function of medium (4467)(4520).
The aryl polyether that is prepared by the reaction of the disodium salt of bisphenol A with 4,4'-dichlorodiphenyl sulfone in DMSO depends
on the moisture content of the polymerizing system. In the presence of water, hydrolysis of 4,4'-dichlorodiphenyl sulfone monomer occurs
concomitant with the polymerization (4704).
The reaction of 2,8-dibromo-5,5-dioxodibenzothiophene with aqueous potassium hydroxide in DMSO gives 8-bromo-2-hydroxy-5,5dibenzothiophene (7709):
Br
Br
OH
Br
aq. DMSO
+ KOH
110o C
S
S
3 hours
O2
O2
Several 4-halogenophenyl sulfonylphenols, useful for the synthesis of poly(arylene ether sulfones), have been prepared by partial
hydrolysis of the corresponding dihalides in DMSO (8825):
X
SO 2
R
aq. DMSO
X + 2KOH
x=halogens
o
60 C
24 hrs.
O2
S
X
R
OK + KX
R
85
c) Amide hydrolysis
The rates of base catalyzed hydrolysis of anilides have been studied in DMSO-water (3820)(7573)(8696). Even a very small amount of
DMSO (less than 1 %) facilitates the kinetic measurements in the hydrolysis of p-nitro- and pformylacetanilide (3820). Some increase
with increasing DMSO has been found in the hydrolysis rate of trifluoroacetanilide (7573).
The reaction of e-caprolatam with barium hydroxide in DMSO-water gives e -aminocaproic acid on acidification
(4972):
H
N
O
Ba (OH)2, DMSO
+H2O
H2N(CH2)5CO2H
95-103 o C
4 hrs.
d) Epoxide hydrolysis
The most commonly encountered reactions of epoxides are those in which the ring is opened by a nucleophile. Such reactions are
advantageously performed in DMSO because DMSO is inert to the epoxides and it also provides maximum reactivity for the nucleophile.
When the relatively unreactive 1 -phenylcyclohexene oxide is heated with potassium hydroxide in aqueous DMSO, the corresponding
trans-glycol is obtained in fairly good yield (334):
Ph
Ph
O
KOH, DMSO
OH
100 o C
OH
+ H 2O
6 hrs
60%
In the presence of acids a mixture of cis- and trans glycols results. The same reaction in aqueous dioxane after48 hours at 150°C gives
only a 10% yield (334).
Treatment of 8,9-epoxyundec-5-en-ol with potassium hydroxide in refluxing aqueous DMSO produces undeca-4,6-diene-3,9-diol (8261):
OH
OH
O
CH2H5 CH-CHCH 2CH=CHCH 2CH2H5+H2O KOH, DMSO
OH
C2 H5 CCH2CH=CHCH=CHCC 2H5
The same treatment of the saturated epoxide, 8,9-epoxy-undecan-3-ol, leads to simple cleavage of the epoxy ring giving undecane3,4,9-triol (8261):
OH
HO OH
C2H5-CH-CH(CH 2)4 CHC2 H5
KOH, DMSO
C2H5CH-CH(CH 2) 4CHC2 H5+H2O
1 -(ß, ? -Epoxypropyl)cyclohexan-1 -ol, when treated with base in 75% aqueous DMSO, gives the corresponding oxetan as the main
product (8306):
+H2O
OH-, DMSO
CH2
OH
OH
49%
e) Ether hydrolysis
When water, strong acid, and ethyl vinyl ether are all solutes in DMSO, the rate of hydrolysis of the vinyl ether is still controlled by the rate
of proton transfer to the carbon. The rate decreases with increasing DMSO concentration (2492)(7643):
CH 2=CHOC 2H5 + H 2O
H+, DMSO
CH 3CHO+C 2H 5OH
The rate coefficients for the alkaline hydrolysis of 4-substituted 1-methoxy-2-nitrobenzenes and 1-alkoxy 2,4 dinitrobenzenes have been
measured in aqueous DMSO. These rates have been correlated with the acidity function of the medium (4467)(4520):
OR
OR
OH
OH
NO 2
NO 2
aq. DMSO
NO 2
+ OH-
NO 2
NO 2
NO 2
A similar study has been done with substituted 2-alkoxytropones in 40% aqueous DMSO (4521).
2,4,6-Trinitroanisole and 2,4,6-trinitrophenyl phenyl ether react with DMSO to give 2,4,6-trinitrophenol and methanol and phenol, resp.
(6878):
86
OR
OH
NO 2
NO 2
NO 2
NO 2
+ ROH
DMSO
NO 2
NO 2
R= Me, Ph
f) Nitrile hydrolysis
Powdered anhydrous sodium hydroxide and potassium hydroxide in DMSO can be used to convert nitriles to amides, e.g. benzonitrile to
benzamide, at a reaction rate that is approximately 10,000 times that in aqueous caustic. However, the solubility of the dry caustic in
DMSO is very low which reduces the speed of converting the nitrile (725).
The reaction of 5-chloro-1,4-diphenyl-1,2,3-triazole with sodium cyanide in moist DMSO gives 1,4-diphenyl1,2,3-triazole-5-carboxamide
due to hydrolysis of the nitrile (7115):
Ph
Ph
N
N
Cl + NaCN + H 2O
N
DMSO
N
N
COHN 2
N
Ph
Ph
g) Saponification
In the base catalyzed hydrolysis of esters in aqueous DMSO, the rate of hydrolysis increases as the mole fraction of DMSO in the mixture
increases. This increase is particularly rapid above 0.7 mol fraction of DMSO (336)(367)(369) (464)(726)(730).
The use of DMSO-water as a solvent for saponification increases the reaction rate difference between the first and second group of
diesters. In 50% aqueous DMSO (v/v) the first ester group can be hydrolyzed more than nine times faster than the second one (1694).
There is a considerable rate enhancement for both steps in alkaline hydrolysis of a series of dicarboxylic acid esters in DMSO-water. The
rates increase with increasing amount of DMSO and these rates are larger in aqueous DMSO than in aqueous ethanol (5969)(6543) or
aqueous acetonitrile (5459).
When the saponification of glycol monobenzoates are carried out in 80% aqueous DMSO, 80% aqueous ethanol and 80% aqueous
acetone, the rates are up to 1000 times faster in 80% aqueous DMSO than in the other two solvent systems (5622):
CH2OH
OH-, DMSO
+ H2O
Ph-CO2H2C
CH2OH
+ HO2C-Ph
30o C
CH2OH
Similarly, the saponification rates of unsaturated esters in DMSO-water are faster than in ethanol-water (3356) (7540). Increased transition
state solvation, not increased hydroxyl ion desolvation, is the major cause of rate enhancement in DMSO (6822).
The rate coefficients of neutral hydrolysis of methyl trifluoroacetate and chloromethyl dichloroacetate in DMSOwater are greater than in
acetone-water and acetonitrile-water (6477).
With hydrolysis on the acid side, however, the reaction rate decreases as the mole fraction of DMSO increases above 25-30% DMSO,
as is the case with ethyl acetate (368).
The cleavage of highly hindered esters can be accomplished in DMSO using potassium t-butoxide as the base and heating until the
cleavage is accomplished. In this case, the cleavage occurs by alkyl-oxygen fission (490). Esters are also cleaved by sodium
superoxide in DMSO to give carboxylic acids in excellent yield, as is the case of
ethyl p-cyanobenzoate (10086).
O
NC
CO2Et + O2-
DMSO
5 min.
H 2NC
CO2H
96%
2. Alcoholysis, Aminolysis
In the basic methanolysis of some aryl substituted N-methyl-2,2,2-trifluoroacetanilides in DMSO-methanol rate increases with increasing
amount of DMSO (6474):
CH3
R
OCH3OH9 DMSO
CH3OH
H 3C N
R-C6H 4NCOCF3 + CH 3OCF3
CH3
R-C6H 4-NH
O
C 6H4
OCH3
+ F3CCOCH3
87
N-Methyl-4'-nitroanilides undergo basic methanolysis by way of rate determining methoxide addition to the amide, as shown above. The
addition of DMSO produces a rate increase in each case (7844).
The mechanism of basic methanolysis of a series of N-aryl-N-phenylbenzamides in methanol and in 80% DMSOmethanol has been
studied. In methanol the rate determining step seems to be the solvent assisted C-N bond breaking, while in 80% DMSO-methanol the
rate determining step is methoxide attack (10409).
Markedly increased alcoholysis rates are obtained by the addition of DMSO to ethylene-vinyl ester interpolymer alcohol mixtures in the
presence of either alkaline or acidic mixtures (7156).
DMSO is an effective catalyst for the n-butylaminolysis of p-nitrophenyl acetate in chlorobenzene (6988).
O
NO2
chlorobenzene, DMSO
O
NO2
+NH2(CH2)3CH3
O
25 o C
O
H3 C
NH(CH2)3CH3 +
-
OH
O
NO2
The aminolysis of polymeric macronet N-hydroxy-succinimide esters of Boc-amino acids by free amino acids and peptides in DMSO has
been studied, both in the presence and in the absence of organic bases (8832).
3. Transesterification (Ester Interchange)
The reported work concerning the base catalyzed transesterification of fatty acid esters mainly describes esterification of carbohydrates
and other polyhydroxylic materials. DMSO is a particularly suitable solvent in this area because of the enhanced activity of the base
catalyst in DMSO and also because of the excellent solubility of most carbohydrate and polyhydroxylic substances in DMSO. A number of
the reports are concerned with sucrose esters (160)(161)(181)(162)(164)(165). Others report esterifying hexitols and hexoses (1257) and
inositols (166). The reaction of 1,2-0-isopropylidene-6-tosyl-glucose under the conditions of the Kornblum oxidation with potassium
bicarbonate as the base gives none of the expected aldehyde but only the 5,6-carbonate ester(183) in a transesterification.
Alkylation of methyl 0-(tetrahydropyran-2-yl) mandelate using alkyl halides and sodium hydride in DMSO at 80°C produces
transesterification products (4278):
OH
O
O
C CO CH
2
3
H
H2CSOCH3, DMSO
+
CHCO 2R
RX
80 o C
R = benzyl, isopropyl, allyl, n-pentyl or cyclopentyl
Dimethyl terephthalate can be polymerized with ethylene glycol in the presence of a tin chloride-DMSO complex and trimethylphosphate
to give a poly(ethylene terephthalate) (7255).
Thermoplastic polymers derived from natural products have been prepared by interesterifying starch with methyl palmitate in DMSO with
potassium methoxide as the catalyst (8227).
PART V USES
1. Polymerization and Spinning Solvent
DMSO is used as a solvent for the polymerization of acrylonitrile and other vinyl monomers, e.g. methyl methacrylate (9638) and styrene
(5192). Acrylonitrile is readily soluble in DMSO and the polymerization is carried out by the addition of initiators (8184)(8185). The low
incidence of transfer from the growing chain to DMSO leads to high molecular weights. Copolymerization reactions of acrylonitrile with
other vinyl monomers can also be run in DMSO. Monomer mixtures consisting of acrylonitrile, styrene, vinylidene chloride, methallyl
sulfonic acid, styrene sulfonic acid, etc. are polymerized in DMSO-water (6713). In some cases, the fibers are spun from the reaction
solution into DMSO-water baths (8501)(8603).
DMSO can also be used as a reaction solvent for other polymerizations. Thus, ethylene oxide is rapidly and completely polymerized in
DMSO (9652). Diisocyanates and polyols and polyamines can be dissolved and reacted in DMSO to form solutions of polyurethanes
(8677).
Polymerization Solvent for Heat Resistant Polymers. Poly(ether sulfones) are a family of polymers from which a series of tough
thermoplastics can be selected for use under continuous stress in the temperature range of 150-250 °C (7196)(7619). These poly(ether
sulfones) are prepared by reacting dialkali metal salts of a bisphenol, such as bisphenol A or 4,4'-sulfonyldiphenol with 4,4'dihyalodiphenyl sulfones by the displacementetherification reaction in DMSO (7104)(9961), e.g.:
88
DM SO
Cl
SO 2
Cl + NaO
SO 2
ONa
O
S
n
O2
Interest in heat-resistant polymers has also lead to the development of polyetherimides. These polymers are prepared by the reaction of
a dialkali metal salt of a bisphenol, such as bisphenol A or 4,4'-sulfonyl diphenol, with bis(halophthalimide) in DMSO as the solvent
(9686). In place of bis(halophthalimides), certain bis(nitrophthalimides) in DMSO can be used (10434):
O
O
N
O
N
S
O
DMSO
+
NaO
O O
X
X= halogen or NO2.
X
ONa
X
O
O
S
O
N
N
O n
O
O O
Somewhat similar polyetherimides can be prepared by reacting an aromatic bis(ether dicarboxylic acid) component with a diamine in
DMSO-water (10762):
X
X
O
O
HO 2C
HO 2C
CO2H
+
H2N
CO2H
NH2
X
O
O
O
O
N
N
X= S; SO 2, CH2, C(CH3)2 , etc.
O
O
X
x-S; SO 2; CH2 ; C(CH3)2, etc
2. Extraction Solvent
DMSO is immiscible with alkanes but a good solvent for most unsaturated and polar compounds. Thus it can be used to separate olefins
from paraffins (10771). DMSO is used in the Institute Francais du Petrole (IFP) process for extracting aromatic hydrocarbons from
refinery streams (8554). DMSO is also used in the analytical procedure for determining polynuclear hydrocarbons in food additives of
petroleum origin (2371).
3. Solvent for Electrolytic Reactions
DMSO has been widely used as a solvent for polarographic studies and it permits the use of a more negative cathode potential than in
water. In DMSO cations can be successfully reduced to form metals that would react with water. Thus, the following metals have been
electrodeposited from their salts in DMSO: cerium (1749), actinides (2520), iron, nickel, cobalt, manganese – all amorphous deposits;
zinc, cadmium, tin, bismuth – all crystalline deposits; (5488); chromium (6672), silver (7459), lead (9175), copper (9396), titanium
(7260). Generally, no metal less noble than zinc, such as magnesium or aluminum, can be deposited from DMSO.
4. Cellulose Solvent
Although DMSO by itself does not dissolve cellulose, the following binary and ternary systems are listed as cellulose solvents: DMSOmethylamine, DMSO-sulfur trioxide, DMSO-carbon disulfide-amine, DMSO-ammoniasodamide, DMSO-dinitrogen tetroxide, DMSOparaformaldehyde (8970)(10368), DMSO-sulfur dioxide-ammonia (9541). A least a ratio of 3 moles of active agent per mole of glucose unit
is necessary for complete dissolution (8970). While only 80% of cellulose dissolves in DMSO-methylamine under cold anhydrous
conditions (10368), DMSO-nitrogen tetroxide is a better solvent, particularly when a small quantity of water is added (9170). Most of these
systems are capable of producting cellulose fibers. The recently discovered DMSO-paraformaldehyde system does not degrade cellulose
and it can form solutions containing up to 10% cellulose (7763)(8506)(9850). It is believed that a methylol-cellulose compound forms which
is stable for extended periods of storage at ambient conditions (9850). Regenerated cellulose articles such as films and fibers can be
prepared by contacting the DMSO-paraformaldehyde solution with methanol and water (9850)(9895).
89
5. Pesticide Solvent
Many organic fungicides, insecticides and herbicides are soluble in DMSO, including such difficultly soluble materials as the substituted
ureas and carbamates. DMSO forms cosolvent systems of enhanced solubility properties with many solvents.
6. Cleanup Solvent
DMSO is used to remove urethane polymers and other difficultly soluble materials from processing equipment. Hard crusts of poly(vinyl
chloride) resin can be dissolved by using 85:15 ethyl acetate-DMSO mixture (8927).
7. Sulfiding Agent
DMSO (ENVIRO-S) can be used as a sulfiding agent in refineries because of its low odor, low toxicity and ease of handling.
8. Integrated Circuits
DMSO solutions are useful for etching resists in integrated circuit manufacture.
PART VI
TOXICITY, HANDLING, HAZARDS, ANALYSIS
1. Toxicity and Handling Precautions
Dimethyl sulfoxide is a relatively stable solvent of low toxicity. The LD50, for single dose oral administration to rats is about 18,000 mg/kg.
For comparison, the LD50 for ethyl alcohol is about 13,700 mg/kg. DMSO by itself presents less hazard than many chemicals and solvents
commonly used in industry. However, DMSO has the ability to penetrate the skin and may carry with it certain chemicals with which it is
combined under certain conditions.
The toxicity of DMSO solutions will depend, in part, on the nature and toxicity of the other chemicals used and the degree of penetration.
The degree of penetration is determined by the concentration of DMSO and water in the solution and the length of time of skin contact.
Not all chemicals will be carried through the skin even though the DMSO may penetrate. A 10% solution of DMSO in water causes only
slight increase in skin penetration over the same solution without DMSO.
Conventional industrial safety procedures and practices should be observed when working with DMSO as with any organic solvent.
Protective clothing is not necessary when handling DMSO in containers or in small amounts on limited occasions. However, when working
with DMSO on a prolonged basis or in combinations with other materials, protective clothing is recommended, including suitable gloves or
eye protectants. Butyl rubber gloves are suggested for DMSO service.
Contacts with DMSO Alone
Skin: Undiluted DMSO may have a mildly irritating effect on the skin and should be washed off promptly with cold water. As is the case
with other organic solvents, dimethyl sulfoxide tends to dehydrate and de-fat the skin. Repeated skin contact overextended periods should
be avoided since the effects of such contact, if any, are not yet known.
Eyes: DMSO in contact with the eye may cause temporary irritation but will not result in eye damage if washed out
promptly with cold
water.
Vapors: The normal ambient airborne DMSO concentration is low. (DMSO has a high boiling point, 189°C or 372°F, and a low vapor
pressure.) Inhalation of vapors of hot DMSO or DMSO aerosol mists may be harmful and should be avoided.
Contact with DMSO solutions: When handling solutions of possibly toxic substances in DMSO, care must be taken to avoid contact with
the skin and to wash such solutions off immediately and thoroughly with soap and water. If toxic substances penetrate into the system,
serious harm may occur. Clothing contacted by such solutions should be removed and washed before reusing.
90
2. Comparative Toxicity of Commercial Solvents
All solvents are toxic to some extent, but DMSO is much less so than many in common usage. Toxicity, as measured by dermal and
oral LD50 in rats, is shown for a number of common solvents. They are listed in order of increasing oral toxicity.
TABLE XII
Single-Dose Toxicity (Rats) of Some Common Solvents
LD50, mg/kg
Solvent
Oral
Dermal
Glycerine
31600
10000
DMSO
17400
40000
Ethanol
13700
Acetone
9750
Dimethylacetamide
7500
5000
Ethylene glycol
7200
N-methyl-2-pyrrolidone
7000
Trichloroethylene
5860
Lsopropanol
5840
n-Propanol
4300
Benzene
4080
Diacetone alcohol
4000
Methyl ethyl ketone
3980
Xylene
3830
10000
Cyclohexanone
3460
Acetic acid
3310
n-Butenol
2610
5620
2-Heptanol
2580
Butyl cellosolve
2380
Dimethylformamide
2250
442
Sodium lauryl sulfate
1650
10000
Pyridine
891
1120
Aniline
442
1540
Phenol
14*
* Approximate lethal dose.
Most of the solvents in the above table were chosen because, like DMSO, they are polar.
Several studies have been made in comparing the toxicity of DMSO with other solvents. Table XIII shows the results of
one of these studies.
TABLE XIII
Single-Dose Toxicities to Mice of 4M Solutions
LD50, mg/kg (mice)
Compound
DMSO
Intravenous
7176
Intraperitoneal
14664
Glycerine
6164
6900
Dimethyl formamide
3650
6570
Dimethyl acetamide
3915
5916
N-methyl pyrrolidone
1980
3564
3. Chemicals and Reactions to be Avoided with DMSO
DMSO can react vigorously and even explosively with iodine pentafluoride, periodic acid, potassium permanganate, silver fluoride and
other strong oxidizing agents such as magnesium perchlorate and perchloric acid.
DMSO cannot be used in Friedel-Crafts reactions or with Ziegler-Natta catalysts.
DMSO reacts vigorously with acid chlorides. These reactions proceed with about the same vigor as the reaction between acid
chlorides and ethyl alcohol, and suitable precautions should be taken.
DMSO also reacts with carboxylic acid anhydrides, such as acetic anhydride, the major product being the
acyloxymethyl methyl sulfide, RCO2CH2SCH3.
Adequate heat removal should be provided when reacting DMSO with sodium hydride or potassium hydride when making the
DMSO anion (dimsyl ion) (Please see PART III, Reactions of DMSO, 4. Reaction with Strong
Bases).
An uncontrolled reaction took place when DMSO was heated with methyl bromide to prepare trimethyloxosulfonium bromide. This
91
reaction should be run in the presence of compounds that remove HBr or Br2, such as methyl or ethyl orthoformate or tetramethyl
orthocarbonate. These esters act as scavengers of HBr and Br2, produced as byproducts in the reaction. Thus, the possible
violent exothermic decomposition of the reaction mixture can be prevented with little, if any, loss in the yield of the product (9964).
4. Analytical Procedure
a) Gas chromatographic analysis of DMSO
Apparatus
Gas chromatograph with flame ionization detector and a 4 ft. x 1/8 inch o.d. stainless steel column packed with 15% FFAP
(Varian Aerograph) on Chromosorb T (Johns -Manville), 40/60 mesh.
1.0 microliter syringe.
Chromatograph Conditions
Temperatures: Column - 150°C, Detector - 220°C, Inlet - 210°C Carrier gas flow 30 ml/min
Adjust the instrument sensitivity so that a 0.5 microliter sample will give a DMSO peak between 75 and 100% of recorder full
scale.
Procedure
Inject 0.5 microliters of the DMSO. Record the DMSO peak at the sensitivity determined above. Record the period before and
after the DMSO peak at 100 times this sensitivity. Record the chromatogram for 20 minutes. Sum the areas of any extraneous
peaks.
Calculations
b) DMSO Freezing Point
Pour 30-50 ml of DMSO into a clean, dry test tube, approximately 2.5x20 cm in size and fitted with a stopper
containing thermometer and also containing a small magnetic stirring bar.
Cool the test tube in water at 15°C while agitating with a magnetic stirrer until crystallization starts. Once crystallization has
begun read the thermometer while both liquid and solid DMSO are present. Purified DMSO - 18.3 °C minimum (See Figure
2b, page 5)
c) Water Determination by Karl Fischer Titration
Discussion
Water is determined by Karl Fischer titration. Karl Fischer procedures other than the one described below may be used provided
that their accuracy in this analysis has been determined.
Scope
This procedure may be used with all grades of DMSO.
Reagents
1. Pyridine-SO2-methanol.
Mix 300 ml. C.P. pyridine and 300 ml anhydrous methanol. Bubble in 60 grams of SO2. This can be done
with the solution on a platform balance to weigh directly the SO2 added.
2. Anhydrous methanol.
3. Karl Fischer Reagent - stablilized.
Fischer Scientific SO-K-3
4. Water-methanol standard.
1 ml = 1 mg of water. Can be obtained commercially.
Apparatus
Titration Assembly
The titration is contained in a screwcap glass jar of 100-200 ml capacity. The cap is drilled to admit2 platinum electrodes and one
burette tip. During the titration the jar is mounted over a magnetic stirrer with the electrodes extending through the cap into the solution
to be titrated. Reagents and sample are added through the third hole and a micro burette containing Karl Fischer Reagent is mounted
above the third hole.
A preferred alternate to the above assembly can be constructed from both halves of a large diameter glass ball and socket joint.
End-Point Detecting Assembly
The end-point detecting assembly is of the "dead stop" type, which depends upon the depolarization of the electrodes on reaching the
end-point of the titration.
92
Procedure
End-Point Detection
With the equipment set up as described and the material to be titrated in the bottle, start the magnetic stirrer. Adjust the variable
resistance to produce a microammeter deflection of 1 or 2 microamps. Titrate with Karl Fischer Reagent. As the end-point is neared,
the ammeter needle starts to swing with each addition of titrant, but returns to the original point of deflection after each swing. When
the end-point is reached the needle will remain permanently displaced up scale.
Standardization of Reagents
The Karl Fischer solution must be standardized daily. Add 20 ml of anhydrous methanol and 5 ml of the pyridine-SO2-methanol
solution to the titration bottle (Note 1). Add Karl Fischer Reagent dropwise from a microburette to the end-point. Accurately pipette 20
ml of the water-methanol standard (a weighed amount of pure water may be used) into the titration bottle and titrate with Karl Fischer
Reagent to the end-point. Record the volume of titrant used in the second titration and calculate its water equivalence.
Determination of Water
Add 20 ml of anhydrous methanol and 5 ml of the pyridine-SO2-methanol solution to a clean titration bottle. Add Karl Fischer Reagent
dropwise to the end-point. Add 2 to 3 grams (accurately weighed) of the DMSO to be tested (Notes 2, 3, and 4). Titrate with Karl
Fischer Reagent to the end-point. Record the volume of titrant used in the second titration and calculate the water content of the
dimethyl sulfoxide.
Notes
1. Response tends to be slow with the stabilized Karl Fischer Reagent. A sharper end-point is obtained with the addition of the
pyridine-SO2-methanol solution to the titration vessel.
2. DMSO is extremely hydroscopic. Exposure of the sample to atmospheric moisture must be kept to a minimum.
3. Samples larger than 2-3 grams of DMSO produce low results.
4. For convenience, with a sacrifice of accuracy, a 2 or 3 ml. volume of DMSO can be sampled with a volumetric pipette. The weight
of DMSO samples is calculated by multiplying the volume in ml. by 1.10 (the specific gravity of pure DMSO @ 20°C.).
5. A titration assembly such as a Beckman Model KF-2 Aquameter may be used for the titration.
PART VII
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4812
4815
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4891
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Wilczynski, J. J.; Johnson, H. W. Jr. J. Org. Chem. 39, 1909-1915 (1974).
Griffith, J. R.; O’Rear, J. G. Synthesis, 493 (1974).
Ryan, M. D.; Evans, D. H. J. Electrochem. Soc. 121, 881-883 (1974).
Krapcho, A. P. Synthesis 383-419 (1974).
Nakagawa, S.; Takehara, Z.; Yoshizawa, S. Denki Kagaku 41, 880-883 (1973); CA 80 151,
952Q.
Vitali, R.; Gladiali, S.; Gardi, R. Gazz. Chim. Ital. 102, 673-678 (1972); Synthesis 454
(1974).
Mariano, P. S.; Watson, D. J. Org. Chem. 39, 2774-2778 (1974).
Boeckman, R. K. Jr.; Ganem, B. Tetrahedron Lett. 913 (1974); Synthesis, 748 (1974).
Wu, M.-C.; Anderson, L.; Slife, C. W.; Jensen, L. J. J. Org. Chem. 39. 3014-3020 (1974).
Brand, W. W.; Bullock, M. W. U.S. 3,842,096 (C1. 260-327 M) (Oct. 15, 1974).
Thummel, R. P. J. Chem. Soc. Chem. Commun. 899-900 (1974).
Ghera, E.; Shoua, S. Tetrahedron Lett. 3843-3846 (1974).
Balakrishnan, M.; Rao, G. V.; Venkatasubramanian, N. J. Indian Chem. Soc. 51, 537-539
(1974).
Tokoroyama, T.; Matsuo, K.; Kanazawa, R.; Kotsuki, H.; Kubota, T. Tetrahedron Lett. 30933096 (1974).
Mully, M.; Zsindely, J.; Schmid, H. Chimia 28, 62 (1974); Synthesis, 604 (1974).
Gulbenk, A. H.; Horne, D. J.; Johnston, H. U.S. 3,746,707 (C1. 260-243AN; CO 7D) (July
17, 1973); CA 79, 105301H.
Meresaar, U. Acta. Chem. Scand. A28, 656-660 (1974).
Stetter, H.; Schreckenberg, M. Ber. 107, 210-214 (1974); Synthesis, 63 (1975).
Kocienski, P. J. J. Org. Chem. 39, 3285-3296 (1974).
Rao, Y. S.; Filler R. J. Org. Chem. 39, 3304-3305 (1974); Synthesis, 543 (1975); CA 82,
16,473K.
Varkey, T. E.; Whitfield, G. F.; Swern, D. J. Org. Chem. 39, 3365-3372 (1974).
Rose, J. B. Chimia 28, 561-567 (1974).
Fleming, R. H.; Quina, F. H.; Hammond, G. S. J. Am. Chem. Soc. 96, 7738-7741 (1974).
Eliason, R.; Kreevoy, M. M. J. Phys. Chem. 78, 2658-2659 (1974).
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(1974).
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Thompson, R. M.; Duling, I. N. U.S. 3,738,960 (C1. 260-49) (June 12, 1973).
Leslie, V. J.; Newton, A. B.; Rose, J. B. U.S. 3,775,368 (C1. 260-49) (Nov. 27, 1973).
Heath, D. R.; Wirth, J. G. U.S. 3,869,499 (C1. 260-465 F) (March 4, 1975).
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Belanger, A.; Brassard, P. Can. J. Chem. 53, 195-200 (1975).
Doddi, G.; Mencarelli, P.; Stegel, F. J. Chem. Soc. Chem. Commun., 273-274 (1975).
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Pfeffer, P. E.; Silbert, L. S. J. Org. Chem. 41, 1373-1379 (1976).
Firestone, R. A.; Reinhold, D. F.; Sletzinger, M. U.S. 3,401,178 (C1. 260-340.5) (Sept. 10,
1968).
Diem, H.; Dudeck, C.; Lehmenn, G. U.S. 3,966,727 (C1. 260-249.9) (June 29, 1976).
Chinn, L. J.; Desai, B. N.; Zawadzki, J. F. J. Org. Chem. 40, 1328-1331 (1975).
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105
8050
8054
8063
8065
8070
8095
8105
8108
8118
8184
8185
8227
8238
8254
8255
8261
8276
8287
8306
8311
8339
8340
8344
8350
8360
8372
8399
8400
8405
8408
8410
8418
8436
8451
8455
8501
8506
8529
8548
8551
8554
8564
8576
8582
8601
8603
Bartsch, R. A. Accounts Chem. Res. 8, 239-245 (1975).
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Proced. Int. 7, 137-144 (1975).
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(1975).
Jones, E. R. H.; Meakins, G. D.; Miners, J. O.; Wilkins, A. L. J. Chem. Soc. Perkin Trans. I,
2308-2312 (1975).
Cavazza, M.; Biggi, G.; DelCima, F.; Pietra, F. J. Chem. Soc. Perkin Trans. II, 1636-1638
(1975).
Markezich, R. L. U.S. 3,992,406 (C1. 260-326 N) (Nov. 16, 1976).
James, G. G.; Pattenden, G. J. Chem. Soc. Perkin Trans. I, 1476-1479 (1976).
Alumni, S.; Baciocchi, E. J. Chem. Soc. Perkins Trans. 11, 488-491 (1976).
Knipe, A. C.; Sridhar, N. Synthesis, 606-607 (1976).
Aida, T.; Akasaka, T.;Furukawa, N.; Oae, S. Bull. Chem. Soc. Jap. 49, 1117-1121 (1976).
Aida, T.; Akasaka, T.; Furukawa, N.; Oae, S. Bull. Chem. Soc. Jap. 49, 1441-1442 (1976).
Sekiguchi, S.; Tsutsumi, K.; Shizuka, H.; Matsui, K.; Itagaki, T. Bull. Chem. Soc. Jap. 49,
1521-1523 (1976).
Timoto, S.; Taniyasu, T.; Miyake, T.; Okano, M. Bull. Chem. Soc. 49, 1931-1936 (1976).
Uzuki, T.; Takahashi, M.; Komachinya, Y.; Wakamatsu, H. U.S. 3,991,077 (C1. 260-326.14
T) (Nov. 9, 1976).
Kornblum, N.; Cheng, L.; Kerber, R. C.; Kester, M.; Newton, B. M.; Pinnick, H. W.; Smith, R.
G.; Wade, P. A. J. Org. Chem. 41, 1560-1564 (1976).
Padwa, A.; Au, A. J. Am. Chem. Soc. 98, 5581-5590 (1976).
Huang, S. L.; Omura, K.; Swern, D. J. Org. Chem. 41, 3329-3331 (1976); Synthesis, 505
(1977); CA 85-142716S.
Toray Inds. KK Japan. J7 6028-734 (C1. A14F01) (A32 A94) ( Aug. 20, 1976).
Seymour, R. B.; Johnson, E. L. J. Appl. Polym. Sci. 20,3425-3429 (1976).
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I, 2089-2093 (1976).
Kennewell, P. D.; Taylor, J. B. Chem. Soc. Revs. 4, 189-210 (1975).
Bartsch, R. A.; Roberts, D. K. Tetrahedron Lett. 321-322 (1977).
Iwakura, Y.; Uno, K.; Nguyen, C. Makromol. Chem. 175, 2079-90 (1974); CA 81, 152729E
(1974).
Kamino, J.; Okamoto, S. Japan. 73, 29,811 (C1. D 01F) (Sept. 13, 1973); CA81, 38758P
(1974).
106
8658
8677
8683
8685
8690
8696
8714
8717
8735
8759
8766
8779
8809
8825
8830
8832
8833
8838
8843
8861
8867
8885
8888
8906
8923
8927
8951
8953
8954
8955
8960
8970
8984
9096
9107
9135
9138
9142
9142
9145
9150
9170
9175
Nakano, F.; Sugishita, M. Japan. 74 24,057 (C1. C 07C, B 01J) (June 20, 1974); CA 82,
111772R.
Richardson, T.; Hustad, G. O. U.S. 3,658731 (C1. 260-2.5 BD) (April 25, 1972).
Heath, D. R.; Wirth, J. G. U.S. 3,873,593 (C1. 260-465 F) (March 25, 1975).
Heath, D. R.; Takekoshi, T. U.S. 3,879,428 (C1. 260-346.3) (April 22, 1975).
Wasson, B. K.; Williams, H. W. R. U.S. 3,812,150 (C1. 260-326.15; C07D) (May 21,1974);
CA 81, 37585T (1974).
Gani, V.; Viout, P. Tetrahedron 32, 2883-2889 (1976).
Takekoshi, T. U.S. 4,024,110 (C1. 260-47 CZ) (May 17, 1977).
Mueller, W. H. U.S. 4,028,417 (C1. 260-586 C) (June7, 1977).
Szmant, H. H.; Birke, A.; Lau, M. P. J. Am. Chem. Soc. 99, 1863-1871 (1977).
Carson, J. R.; Hortenstine, J. T.; Maryanoff, B. E.; Molinari, A. J. J. Org. Chem. 42, 10961098 (1977).
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18, 354-358 (1977).
Ito, Y.; Fujii, S.; Konoike, T.; Saegusa, T. Synthetic Commun. 6, 429-433 (1976); Sythesis
283 (1977).
Andreev, S. M.; Tsiryapkin, V A.; Samoilova, N. A.; Mironova, N. V.; Davidovich, Y. A.;
Rogozhin, S. V. Synthesis 303-304 (1977).
Mukaiyama,T.; Sato, T.; Suzuki, S.; Inoue, T.; Nakamura, H. Chem. Lett. (1) 95-98 (1976);
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Markgraf, J. H.; Ibsen, M. S.; Kinny, J. B.; Kuper, J. W.; Lurie, J. B.; Marrs, D. R.; McCarthy,
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Kabalka, G. W.; Baker, J. D. Jr.; Neal, G. W. J. Org. Chem. 42, 512-517 (1977).
Hajos, Z. G. U.S. 4,048,195 (C1. 260-345.9 S) (Sept. 13, 1977).
Ritz, J.; Reese, J. Ger. Offen. 2,250,232 (C1. C 07C, C09D) (Apr. 25, 1974); CA 82,
113469W (1975).
Razumovskii, S. D.; Shatokhina, E. L.; Malievskii, A. D.; Zaikov, G. E. Izv. Akad. Nauk.
SSSR, Ser. Khim. 543-546 (1975); CA 82, 169742X (1975).
Carosello, T. F.; Weinberg, J. Ger. Offen. 2,432,685 (C1. C 08F, C 04B, A 01N) (Feb. 6,
1975); CA 82, 171903U.
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Wasson, B. K.; Williams, H. W. R. U.S. 3,944,560 (C1. 260-302H) (March 16, 1976); CA
85, 94415U.
Cresswell, R. M.; Mentha, J. W. U.S. 3,878,252 (C1. 260-607A; C07C) (April 15, 1975);
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Turbak, A. F.; Hammer, R. B.; Portnoy, N. A.; West, A. C. U.S. 4,076,933 (C1. 536-30)
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Kuznetsov, V. V.; Grigor’ev, V. P.; Shpan’ko, S. P.; Bozhenko, L. G. Zashch. Met. 1, 631107
9196
9222
9244
9249
9338
9396
9402
9408
9412
9423
9434
9439
9464
9488
9541
9563
9567
9581
9604
9605
9638
9652
9678
9686
9707
9727
9746
9752
9761
9767
9769
9771
9773
9780
9783
9786
9825
9850
9871
9874
634 (1975); CA 84, 10359X.
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Von Strandtmann, M.; Shavel, J. Jr.; Klutchko, S.; Cohen, M. U.S. 3,937,704 (C1. 260250C; C07D) (Feb. 10, 1976); CA 84, 150650K.
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39046R.
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Voronkov, M. G. Zh. Prikl. Khim. (Leningrad) 51, 117-120 (1978); CA 137048H.
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14, 337-339 (1978); C. A. 88, 169698M.
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Radhakrishnamurti, P. S.; Padhi, S. C. Curr. Sci. 46, 517-518 (1977); CA 87, 183721Z.
Wirht, J. G.; Heath, D. R. U.S. 3,787,364 (C1. 260-61) (Jan. 22, 1974).
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W.P. J. Org. Chem. 43, 138-47 (1978); CA 88, 50032Z.
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Welch, S.C.; Rao, A.S.C.P. J. Org. Chem. 43, 1957-1961 (1978).
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108
9895
9926
9928
9944
9949
9960
9961
9964
9985
9986
10000
10002
10008
10011
10032
10043
10044
10048
10066
10077
10078
10084
10085
10086
10091
10116
10123
10127
10134
10139
10143
10224
10286
10315
10320
10368
10394
10399
10409
10411
10422
10434
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10443
10454
10458
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